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THE  MALARIAL  FEVERS, 
HAEM0GL0BINUK1C  FEVER 


AND 


THE  BLOOD  PROTOZOA  OF  MAN 


BY 


CHARLES  F.  CRAIG,  M.  D. 

Captain,  Medical  Corps,  U.  S.  Army 


ATTENDING    SURGEON,    NEW    YORK    CITY.      LATE    PATHOLOGIST    AND    BACTERIOLOGIST    TO    THE    STERNBERG 
U.     S.     ARMY     GENERAL     HOSPITAL,      CHICKAMAUGA     PARK,    GA.  ;     THE  JOSIAH     SIMPSON     GENERAL 
HOSPTTAL,    FORTRESS    MONROE,    VA. ;    THE  CAMP  COLUMBIA    HOSPITAL,  HAVANA,    CUBA;    THE 
U.   S.  ARMY    GENERAL    HOSPITAL,  PRESIDIO  OF  SAN  FRANCISCO,  CAL.  ;    THE    DIVISION 
HOSPITAL,    MANILA,    P.    I.      LATE    MEMBER     OF    THE    U.    S.    ARMY    BOARD    FOR 
THE    STUDY    OF    TROPICAL   DISEASES    IN    THE     PHILIPPINE    ISLANDS. 
MEMBER     OF     THE     SOCIETY    OF    TROPICAL    MEDICINE   AND 
HYGIENE,     LONDON;     THE     AMERICAN     SOCIETY     OF 
TROPICAL  MEDICINE,  AND  THE  NATIONAL  AS- 
SOCIATION FOR  THE  STUDY  AND  PRE- 
VENTION   OF    TUBERCULOSIS 


ILLUSTRATED  BY  FOUR  COLORED  PLATES 

TWENTY-FIVE  CLINICAL  CHARTS 

AND  TWENTY-EIGHT  PHOTOMICROGRAPHS  AND  DRAWINGS 


NEW   YORK 

WILLIAM  WOOD  AND  COMPANY 

MDCCCCIX 


C?4 


Copyright,  1909 
By  WILLIAM  WOOD  AND  COMPANY 


Printed  by 

The  Maple  Press 

York.  Pa. 


TO    THE    OFFICERS 
OF 

THE   MEDICAL   CORPS 

OF    THE 

UNITED    STATES   ARMY, 

THIS    BOOK   IS   AFFECTIONATELY 
DEDICATED   BY   THE  AUTHOR 


PREFACE. 


While  several  excellent  works  dealing  with  the  laboratory  side  of  the  subject 
have  appeared  within  recent  years,  no  complete  treatise  upon  the  malarial 
fevers  has  been  printed  in  English  since  the  author's  work  entitled  "The 
Aestivo-autumnal  (Remittent)  Malarial  Fevers,"  published  in  1901.  Thayer's 
excellent  monograph  upon  this  subject  in  Allbutt  and  Rolleston's  "System  of 
Medicine"  and  the  author's  in  Osier's  "Modern  Medicine"  consider  the  subject 
but  briefly  from  necessity,  and  the  many  important  discoveries  made  in  the 
etiology  of  these  fevers,  and  the  advances  made  in  the  prophylaxis  of  malarial 
disease  during  the  past  ten  years  are  such  as  to  justify  us  in  the  publication  of 
the  present  work.  The  author  has  endeavored  to  record  in  this  work  all  im- 
portant advances  and  facts  of  interest  to  the  student  and  clinician,  and  to  this 
end  has  consulted  a  mass  of  literature,  the  most  important  papers  being  noted  in 
the  literary  reference  found  at  the  end  of  each  chapter.  For  many  of  these 
references  I  am  indebted  to  the  extensive  bibliographies  in  Thayer  and 
Hewetson's  "Malarial  Fevers,"  of  Baltimore,  and  Zieman's  monograph  upon 
malaria  in  Mense's  "Handbuch  der  Tropenkrankheiten."  In  every  case  the 
author  has  tried  to  give  proper  credit  for  the  observations  quoted,  and  if  he  has 
failed  it  has  not  been  intentionally. 

The  work  is  very  largely  the  result  of  personal  experience  gained  in  the 
United  States  military  hospitals  in  this  country,  Cuba,  and  the  Philippines,  and, 
as  such,  embodies  the  results  of  over  ten  years  of  investigation,  and  the  study  of 
thousands  of  cases  of  malarial  fever.  The  importance  of  a  thorough  under- 
standing of  malarial  disease  cannot  be  overrated,  and  with  the  acquisition  of 
the  Philippine  Islands  and  of  Porto  Rico  it  is  more  imperative  than  ever  that 
the  American  physician  be  able  to  distinguish  these  fevers,  and  properly  treat 
them.  The  author  has  never  changed  his  opinion  that  infinite  suffering  could 
have  been  avoided  and  scores  of  lives  saved  in  our  camps  during  the  Spanish 
War  had  our  physicians  been  thoroughly  familiar  with  the  malarial  fevers, 
especially  the  aestivo-autumnal  infections.  Further  experience  has  only  con- 
firmed his  opinion  that  every  physician  practising  in  malarial  localities  should 
.be  able  to  recognize  the  malarial  plasmodia  in  the  blood  and  that  blood  exami- 
nations should  be  relied  upon  in  the  diagnosis  of  malarial  disease. 

In  addition  to  the  consideration  of  the  malarial  fevers,  the  author  has 
thought  it  best  to  add  chapters  treating  of  haemoglobinuric  fever  and  the  blood 
protozoa  of  man.  While  he  is  of  the  opinion  that  haemoglobinuric  fever  is  a 
disease  suis  generis,  the  fact  that  it  occurs  in  malarial  regions  and  often  compli- 


VI  PREFACE. 

cates  malarial  disease  renders  a  consideration  of  the  condition  necessary  in  any 
complete  work  upon  the  malarial  fevers.  The  chapters  dealing  with  the  blood 
protozoa  have  been  included  in  order  to  make  the  work  complete  as  regards  the 
examination  of  the  blood,  of  so  much  importance  in  the  diagnosis  of  malaria. 
As  the  protozoa  described  occur  in  regions  in  which  the  malarial  fevers  abound 
and  as  these  organisms  might  be  found  in  the  blood  while  examining  this  fluid 
for  the  plasmodia,  the  author  deemed  that  a  brief  description  of  the  blood 
protozoa  of  man  would  prove  of  service  in  a  work  devoted  primarily  to  the 
malarial  fevers. 

The  author  would  indeed  be  ungrateful  were  he  to  omit  expressing  his 
gratitude  to  the  many  officers  of  the  Medical  Corps  of  the  United  States  Army, 
who  have  aided  him,  directly  or  indirectly,  in  the  preparation  of  this  work. 
Brigadier- General  George  H.  Torney,  Surgeon-General,  U.  S.  Army,  has,  by 
his  support  and  encouragement,  placed  the  author  under  many  obligations, 
which  he  can  never  hope  to  repay,  but  which  are  here  thankfully  ac- 
knowledged; to  Major-General  Robert  M.  O'Reilly,  and  Brigadier-Generals 
Sternberg  and  Girard,  the  author  is  indebted  for  opportunities  afforded  for 
the  study  of  the  malarial  fevers;  to  Colonels  G.  B.  Girard  and  Byrne,  and 
Lieutenant-Colonels  Richard,  Crosby,  Carter,  and  Harris,  the  author's  thanks 
are  due  for  encouragement  and  assistance.  The  author  also  desires  to  express 
his  gratitude  to  Colonel  Wm.  B.  Leishman,  of  the  Royal  Army  Medical  Corps, 
to  whom  he  is  indebted  for  literature  and  specimens,  and  to  Professor  Novy, 
of  Ann  Arbor,  for  many  favors. 

The  photomicrographs  were  taken  at  the  Bureau  of  Science,  in  Manila, 
and  to  this  institution,  and  its  director,  Dr.  Paul  Freer,  and  the  director  of  the 
biological  department,  Dr.  Richard  P.  Strong,  the  author  desires  to  express  his 
gratitude  and  appreciation.  It  is  the  earnest  hope  of  the  author  that  this 
volume  may  be  of  value  in  the  elucidation  of  the  fevers  of  tropical  and  sub- 
tropical countries. 

CHARLES  F.  CRAIG. 
New  York,  April  io,  1909. 


CONTENTS. 


PART  I. 

The  Etiology  of  the  Malarial  Fevers. 

Chapter  I. — Synonyms;  Definition;  Historical;  Geographical  Distribution 

of  the  Malarial  Fevers      3 

Chapter  II. — Etiology;  Classification  of  the  Parasites  of  the  Malarial 
Fevers;  Morphology  and  Biology  of  the  Malarial  Plasmodia  in  the 
Blood  of  Man       14 

Chapter  III. — Development  of  the  Malarial  Plasmodia  within  the 
Mosquito:  Mosquitoes;  Structure;  Ova;  Larva?;  Pupa;;  Habits; 
Distribution;  Classification;  Mosquitoes  proven  to  Transmit  Malaria; 
The  Relation  of  Number  of  Infected  Mosquitoes  to  Malarial  Infection 
in  Various  Localities        56 

Chapter  IV. — Methods  of  Transmission  of  the  Malarial  Plasmodia:  by 
the  Atmosphere;  by  Water;  by  Inoculation  of  Malarial  Blood;  by 
Inoculation  by  the  Mosquito;  Cultivation  of  Malarial  Plasmodia; 
Immunity       : 79 

Chapter  V. — Predisposing  Causes,  General  and  Local;  Period  of  Incuba- 
tion of  the  Malarial  Fevers;  Congenital  Malaria 104 

PART  II. 

The  General  and  Special  Pathology  of  the  Malarial  Fevers. 

Chapter  I. — The  General  Pathology  of  the  Malarial  Fevers;  Morphologi- 
cal Changes  in  the  Erythrocytes  and  Leucocytes;  Anaemia;  Differen- 
tial Blood  Count;  Phagocytosis;  Melanaemia;  the  Urine;  the  Etiology 

of  the  Fever 127 

Chapter  II. — The  Special  Pathology  of  Acute  Malarial  Infections.      .    .    .    148 
Chapter  III. — The   Pathology    of    Latent    Malarial    Infections    and    of 

Malarial  Cachexia 161 

PART  III. 

The  Symptomatology  and  Clinical  Varieties  of  the  Malarlal  Fevers. 

Chapter  I. — Clinical  Classification;  Tertian  Malarial  Fever;  Quartan 
Malarial  Fever;  Aestivo-autumnal  Malaria;  Analysis  of  Symptoms; 

Examination  of  the  Blood       169 

vii 


Vlll  CONTENTS. 

Chapter  II. — Clinical  Illustrations  of  the  Tertian  and  Quotidian  Aestivo- 

autumnal  Malarial  Fevers       194 

Chapter  III. — The  Pernicious  Forms  of  the  Malarial  Fevers 215 

Chapter  IV. — Latent  Malaria;  Masked  Malaria;  Recurrent  Malaria; 
Etiology  of  Latency  and  Recurrence;  Intracorpuscular  Conjugation  of 
the  Malarial  Plasmodia 228 

Chapter  V. — Subcontinued  and  Remittent  Malarial  Fevers;  Mixed 
Malarial  Infection;  Chronic  Malarial  Infection  and  Malarial  Cachexia  ; 
Spontaneous  Recovery      252 

PART   IV. 

The  Sequel.e,  Complications,  and  Prognosis  of  the  Malarial  Fevers. 

Chapter  I. — The  Sequeke  of  the  Malarial  Fevers      267 

Chapter  II. — The  Complications  of  the  Malarial  Fevers      276 

Chapter  III. — Coincident  Typhoid  and  Malarial  Infection 284 

Chapter  IV. — The  Prognosis  of  the  Malarial  Fevers 298 

PART  V. 
The  Diagnosis,  Prophylaxis,  and  Treatment  of  the  Malarial  Fevers. 

Chapter  I. — The  Laboratory  Diagnosis  of  the  Malarial  Fevers;  Staining 
Methods;  Examination  of  the  Blood;  Examination  of  Malarial 
Mosquitoes        307 

Chapter  II. — The  Clinical  Diagnosis  of  the  Malarial  Fevers;  the  Differ- 
ential Diagnosis  of  the  Malarial  Fevers  330 

Chapter  III. — The  Prophylaxis  of  the  Malarial  Fevers 342 

Chapter  IV. — The  Treatment  of  the  Malarial  Fevers 360 

PART  VI. 
Fiaemoglobinuric  Fever.  391 

PART  VII. 

The  Blood  Protozoa  of  Man. 

Chapter  I. — The  Leishman-Donovan  Bodies;  Leishmania-donovani      .    .  411 

Chapter  II. — Trypanosoma  Gambiense  (Trypanosoma  Ugandense)      .    .  428 
Chapter  III. — The  Spirochaetes;   Spirochaeta  Recurrentis;   Spirochaeta 

Duttoni;  Spirochaeta  Novyi;  Spirochaeta  Carteri  (Spiroschaudinnia)    .  445 

Chapter  IV. — Histoplasma  Capsulatum         460 

Index  to  Authors 463 

General  Index 469 


LIST  OF  PLATES  AND  ILLUSTRATIONS 


PLATE.  FACING    PAGE 

I.   Species  of  Malarial  Plasmodia,  as  observed  in  the  Blood 26 

II.   Stained  specimens  of  Tertian  and  Quartan  Malarial  Plasmodia 32 

III.  Stained  specimens  of  Tertian  and  Quotidian  Aestivo-autumnal  Plas- 
modia, and  of  the  Gametes  of  the  various  Species  of  Malarial 
Plasmodia 42 

IV.  Leishmania  donovani.  Trypanosoma  gambiense.  Spirochceta  duttoni 
Histoplasma  capsulatum 411 

FIGURE.  PAGE 

1.  Plasmodium  vivax.      Photomicrograph 20 

2.  Plasmodium  vivax.     Photomicrograph 20 

3.  Plasmodium  vivax.      Photomicrograph 25 

4.  Plasmodium  vivax.     Photomicrograph 25 

5.  Plasmodium  vivax.     Photomicrograph 25 

6.  Plasmodium  malarias.     Photomicrograph 29 

7.  Plasmodium  malarias.     Photomicrograph 29 

8.  Plasmodium  malarias.     Photomicrograph 29 

9.  Plasmodium  falciparum  tertianum.      Photomicrograph 38 

10.  Tertian  aestivo-autumnal  "ring  f orm  "  and  microgametocyte.      Photo- 
micrograph    50 

11.  Aestivo-autumnal  tertian  macrogamete.      Photomicrograph 53 

12.  Tertian  aestivo-autumnal  microgametocyte.      Photomicrograph  ....  53 

13.  Development  of  Plasmodium,  vivax  within  the  Mosquito 61 

14.  Comparison  of  Head  of  Anopheles  and  Culex 64 

15.  Venation  of  Wing  in  Anophelinae.     (Modified  from  Theobald) 65 

16.  Internal  Anatomy  of  the  Anophelinae.      (After  Nuttall  and  Shipley)    .  .  66 

17.  Ova  of  Mosquitoes 67 

18.  Larva  of  Anopheles  and  Culex'.      (After  Howard  and  Theobald)    ....  68 

19.  Pupa  of  Anophelinae.      (After  Nuttall  and  Shipley) 71 

20.  Comparison  of  Resting  Position  of  Anopheles  and  Culex 74 

21.  Characters  of  Scales  upon  Mosquitoes 75 

22.  Characteristics  of  Scales,  upon  Various  Species  of  Mosquitoes.  (Arranged 
from  Theobald) 76 

23.  Appearances  in   the   Red    Blood   Cells  which  have  been  mistaken  for 
Plasmodia 311 

24.  Diagram  of  Typical  Anophelina.      (Modified  from  Theobald) 323 

25.  Method  of  Mounting  and  Preserving  Mosquitoes 326 

26.  Leishmania  donovani.      (After  Leishman) 417 

27.  Leishmania  donovani.     Photomicrograph 422 

28.  Trypanosoma  gambiense 435 


IX 


LIST  OF  CLINICAL  CHARTS 


CHART.  PAGE 

A.  Tertian  Malarial  Fever 174 

B.  Quartan  Malarial  Fever 177 

C.  Aestivo-autumnal  Malarial  Fever,  Pneumonic  form 225 

1.  Tertian  Aestivo-autumnal  Malarial  Fever 179 

2.  Tertian  Aestivo-autumnal  Malarial  Fever 181 

3.  Tertian  Aestivo-autumnal  Malarial  Fever 183 

4.  Tertian  Aestivo-autumnal  Malarial  Fever 185 

5.  Quotidian  Aestivo-autumnal  Malarial  Fever 187 

6.  Quotidian  Aestivo-autumnal  Malarial  Fever 196 

7.  Quotidian  Aestivo-autumnal  Malarial  Fever 198 

8.  Quotidian  Aestivo-autumnal  Malarial  Fever 200 

9.  Quotidian  Aestivo-autumnal  Malarial  Fever 202 

10.  Quotidian  Aestivo-autumnal  Malarial  Fever 204 

11.  Tertian  Aestivo-autumnal  Malarial  Fever 206 

12.  Tertian  Aestivo-autumnal  Malarial  Fever 208 

13.  Tertian  Aestivo-autumnal  Malarial  Fever 210 

14.  Tertian  Aestivo-autumnal  Malarial  Fever 211 

15.  Tertian  Aestivo-autumnal  Malarial  Fever 213 

16.  Sub-continued  Aestivo-autumnal  Malarial  Fever 255 

17.  Combined  Tertian  and  Tertian  Aestivo-autumnal  Malaria 257 

17^.   Combined  Quartan  Malarial  Fever  and  Typhoid  Fever 291 

18.  Combined  Typhoid  and  Aestivo-autumnal  Malarial  Fevers 295 

19.  Typhoid  Fever.      Decline 334 

20.  Acute  Tuberculosis  of  Lungs 336 

21.  Infective  Endocarditis.      (After  Dock) 338 


'LIBRAF...        .  TOP 


G« 


.ffiNi  A, 

COLLEGE 


XI 


PART  I 


THE  ETIOLOGY  OF  THE  MALARIAL  FEVERS. 


CHAPTER  I. 

Synonyms;  Definition;  Historical;  Geographical  Distribution  of  the 
Malarial  Fevers. 

Synonyms. — English:  Intermittent  and  Remittent  fevers,  Tertian,  Quartan 
and  Aestivo-autumnal  fevers,  Estivo-autumnal  fever,  Paludal  fever,  Climatic 
fever,  Ague,  Marsh  fever,  Jungle  fever,  Coast  fever,  Mountain  fever,  Hill  fever, 
Swamp  fever,  Cold  fever,  Paludism,  Gnat  fever,  Haemamoebiasis,  Cameroon 
fever.  German:  Wechselfieber.  Dutch:  Koorts.  French:  Paludisme,  Fievre 
paludiene,  Maladies  palustres,  Febbre  intermittente,  Fievre  pernicieuse. 

Definition. — By  the  term  "the  malarial  fevers"  we  mean  a  group  of 
specific  fevers  due  to  infection  of  the  red  blood-corpuscles  of  man  by  closely 
related  animal  parasites  belonging  to  the  Protozoa,  class  Spprozoa,  genus 
Plasmodium. 

Zoologically  considered,  the  malarial  parasites  belong  to  the  Protozoa,  class 
Sporozoa,  order  Haemosporidia,  genus  Plasmodium.  From  a  biological  stand- 
point the  name  Plasmodium,  given  by  Marchiafava  and  Celli  as  a  generic  term 
for  the  organisms  causing  the  malarial  fevers,  is  most  unfortunate,  as  they  are 
not  inhabitants  of  the  blood  plasma  exclusively,  but  pass  the  greater  portion  of 
their  life  cycle  in  man  within  the  erythrocytes.  For  this  reason  the  generic 
name,  Haemamoeba,  suggested  by  Grassi,  is  preferable,  but  the  term  '"Plasmo- 
dium" will  have  to  be  retained  because  of  the  law  of  priority. 

The  same  objection  may  be  raised  to  the  name  "malarial"  first  used  by  the 
Italians,  and  meaning  "bad  air."  This  term  was  applied  to  these  fevers  because 
of  the  supposed  relations  of  miasmatic  conditions  to  their  causation,  but  in  the 
light  of  our  present  knowledge  of  the  etiology  of  this  class  of  fevers,  the  name 
is  erroneous  and,  according  to  some  writers,  should  be  abandoned.  However, 
the  name  has  become  so  firmly  established  in  medical  nomenclature  that,  in 
the  opinion  of  most  authorities,  it  will  have  to  be  retained. 

The  malarial  fevers  occur  epidemically  or  endemically  and  are  accompanied 
by  a  symptom-complex,  which  is  more  or  less  characteristic  of  each  variety. 
Periodicity  is  one  of  the  most  marked  clinical  phenomena,  and  is  due  to  the 
growth  and  sporulation  of  the  plasmodia.  All  varieties  of  malaria  are  distin- 
guished by  yielding  to  quinin,  which  is  also  the  most  efficient  of  prophylactics. 
Biologically,  the  malarial  fevers  may  be  divided  into  tertian,  quartan,  and 
aestivo-autumnal;  clinically,  into  intermittent,  remittent  and  continuous,  but 
the  latter  classification  is  not  scientific  as  it  does  not  indicate  disease  entities, 
but  only  the  type  of  fever  which  may  be  present.  The  malarial  fevers  are  all 
transmitted  by  mosquitoes  belonging  to  the  Anophelince,  and  as  far  as  we  at 
present  know  this  is  the  only  method  of  transmission. 

Historical. — The  history  of  the  malarial  fevers  may  be  divided  into  four 
periods,  as  follows: 

3 


4  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

First  Period.  From  the  earliest  historical  time  to  the  discovery  of  cin- 
chona bark. 

Second  Period.  From  the  discovery  of  cinchona  bark  to  the  discovery 
of  the  plasmodia. 

Third.  Period.  From  the  discovery  of  the  plasmodia  to  the  discovery  of 
the  method  of  transmission  by  the  mosquito. 

Fourth  Period.  From  the  discovery  of  the  method  of  transmission  to 
the  present  time. 

First  Period. — It  is  more  than  probable  that  the  ancient  Egyptians 
possessed  some  knowledge  of  what  are  now  termed  the  "malarial  fevers," 
for,  according  to  W.  Groff,  the  annual  recurrence  of  malaria  is  indicated  in 
inscriptions  upon  the  temple  ruins  at  Denderah.  In  the  fifth  century  B.  C, 
Hippocrates  gave  a  clear  description  of  these  fevers,  distinguishing  them  from 
other  continued  fevers  and  dividing  them  into  tertian,  quartan,  quotidian,  and 
semitertian.  He  recognized  that  the  malarial  fevers  are  most  frequent  in  the 
summer  and  autumn  and  in  the  vicinity  of  bodies  of  water.  Celsus,  in  the 
first  century  A.  D.,  distinguished  the  pernicious  forms  of  malaria,  as  well  as 
the  forms  described  by  Hippocrates.  His  description  of  the  malignant 
tertian  fever  proves  beyond  doubt  that  this  form  of  malaria  was  well  known 
at  the  time  he  wrote.      He  says: 

"But  of  tertians  there  are  two  sorts.  One  commencing  and  terminating 
like  the  quartan,  with  this  difference  only  that  it  affords  one  day's  interval, 
and  returns  on  the  third;  the  other,  far  more  dangerous,  returning,  it  is  true,  on 
the  third  day,  but  generally  occuping  by  the  accession  six-and-thirty  out  of 
the  forty-eight  hours,  sometimes  even  more  or  less;  nor  does  it  entirely  subside 
in  the  remission,  but  only  becomes  mitigated." 

Varro,  Columella,  Avicenna,  and  Palladius  all  described  the  forms  of 
malarial  fever  observed  by  them,  and  regarded  the  emanations  arising  from 
swamps  and  the  swarms  of  minute  animals  present  in  swamp  water  as  probable 
causes  of  certain  forms  of  malaria.  .During  the  years  of  Roman  sovereignty 
enormous  aqueducts  were  constructed  and  drainage  works  undertaken  for 
the  sole  purpose  of  rendering  Italy  free  from  the  terrible  scourge  of  malaria, 
and  that  many  of  these  operations  were  successful  is  proven  by  the  ruins  of 
once  populous  cities  in  localities  which  to-day  are  uninhabitable  on  account  of 
the  prevalence  of  these  fevers. 

During  the  darkness  and  superstition  of  the  Middle  Ages  no  additions  were 
made  to  our  knowledge  of  malaria  and  it  was  not  until  the  middle  of  the  17  th 
century,  when  cinchona  bark  was  introduced  into  Europe,  that  an  impetus 
was  given  to  the  study  of  these  fevers. 

Second  Period. — Cinchona  bark  was  introduced  into  Europe  in  1640 
by  the  Viceroy  del  Cinchon,  who  had  observed  its  action  in  Ecuador  in  natives, 
and  Europeans  suffering  from  malaria.  The  introduction  of  this  drug  greatly 
stimulated  the  study  of  the  malarial  fevers,  as  by  its  use  it  was  possible  to  distin- 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  5 

guish  these  fevers  from  other  diseases,  and  to  Morton,  Sydenham,  Lancisi, 
and  Torti,  we  owe  much  of  our  knowledge  regarding  the  clinical  symptoms 
of  these  fevers.  Morton,  of  London,  in  1697,  described  minutely  the  pernicious 
fevers  of  malarial  origin,  recognized  the  specific  action  of  cinchona  bark,  and 
believed  that  the  emanations  from  swamps  and  marshes  had  much  to  do  with 
their  causation.  Lancisi,  in  1 717,  published  an  elaborate  study  upon  the  etiology 
of  the  malarial  fevers,  in  which  he  considered  that  they  were  due  to  inorganic 
and  organic  substances  found  in  the  air  of  marshy  districts,  and  even  suspected 
that  insects,  such  as  mosquitoes,  might  transmit  these  fevers.  In  1723, 
Sydenham  described  the  intermittent  forms  of  malaria  and  recognized  the 
specific  action  of  cinchona.  Torti,  in  1753,  published  a  classical  treatise  upon 
these  fevers  in  which,  for  the  first  time,  the  term  "malaria,"  destined  to  distin- 
guish these  infections,  was  used.  Meckel,  in  1847,  described  the  pigmented 
leucocytes  so  often  observed  in  malarial  blood,  while  Frerichs  and  Virchow 
confirmed  his  results.  It  is  very  probable,  from  their  descriptions,  that  the 
latter  investigators  actually  saw  the  malarial  plasmodia,  but  did  not  recognize 
their  true  nature. 

With  the  perfection  of  the  compound  microscope  there  was  rendered 
visible  to  the  eye  of  man  a  hitherto  invisible  world  of  living  creatures  and  a 
new  era  began  in  the  study  of  the  etiology  of  disease.  While  the  theory  that 
the  malarial  fevers  might  be  due  to  parasitic  infection  was  very  ancient,  Varo, 
(B.  C.  1 29-1 18)  having  conjectured  that  the  cause  might  be  minute  animal 
life  in  some  form,  the  only  observer  who  had  definitely  declared  his  belief  that 
invisible  organisms  were  the  cause  of  malaria  was  Lancisi,  and  it  was  not  until 
1849,  when  J.  K.  Mitchell  suggested  that  certain  spores  occuring  in  marshy 
districts  might  be  the  etiological  factor,  that  attention  was  forcibly  directed 
to  the  relation  micro-organisms  might  bear  to  these  fevers. 

Following  Mitchell's  suggestion,  Salisbury,  in  1866,  described  certain 
small  vegetable  cells  of  the  family  Palmella,  which  he  found  in  the  soil  of  malarial 
localities  upon  the  banks  of  the  Ohio  and  Mississippi  Rivers,  and  which  he  be- 
lieved to  be  the  cause  of  malaria.  He  claimed  that  these  spores  rose  into 
the  air  at  night  and  fell  to  the  ground  at  sunrise,  thus  explaining  the  danger 
of  night  air,  and  the  inocuousness  of  the  air  during  the  day  in  malarial  regions. 
He  also  claimed  to  have  demonstrated  the  same  spores  in  the  urine  and 
perspiration  of  persons  suffering  from  malaria,  and  for  a  considerable  period 
his  observations  were  accepted,  and  the  spores  of  Palmella  were  regarded  as 
the  cause  of  these  fevers. 

In  1879,  after  the  results  of  Salisbury  had  been  shown  to  be  erroneous, 
Klebs  and  Tommasi-Crudeli  announced  their  discovery  of  the  Bacillus  malarice, 
a  bacillus  found  in  the  water  and  soil  of  malarious  regions,  capable  of  cultiva- 
tion upon  ordinary  culture  media,  and  producing,  when  injected  in  man,  in 
pure  culture,  undoubted  symptoms  of  malarial  infection.  The  observations 
of  these  investigators,  while  never  confirmed  by  careful  workers,  were  accepted 
as  true  by  a  large  proportion  of  the  scientific  world,  and  such  authorities  as 


6  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

Marchifava  and  Cuboni  claimed  to  have  found  this  bacillus  in  the  blood  of 
their  malarial  patients.  The  final  discovery,  in  1880,  of  the  true  cause  of  malaria, 
although  not  generally  admitted  until  1884,  proved  that  the  bacillus  of  Klebs 
and  Tommasi-Crudeli  stood  in  no  causative  relation  to  the  malarial  fevers, 
and  affords  us  an  illustration  of  the  fallibility  of  human  judgment  in  scientific 
research. 

Third  Period. — In  1880,  Laveran,  a  French  army  surgeon,  working  in 
Constantine,  Algeria,  described  certain  parasites  occurring  in  the  blood  of 
malarial  patients  which  he  considered  to  be  the  cause  of  the  disease.  His 
first  communication  was  made  to  the  Academy  of  Medicine  in  Paris,  and  was 
followed  in  1881  by  a  more  detailed  description  of  the  organism.  He  described 
three  forms  of  the  parasite.  The  first  consisted  of  oval  or  crescentic  bodies 
with  hyaline  protoplasm  containing  pigment,  arranged  either  in  clumps  or  in  a 
wreath-like  form.  This  was  undoubtedly  the  crescentic  form  of  the  aestivo- 
autumnal  plasmodium.  The  second  form  described  consisted  of  small  hyaline 
bodies  containing  pigment,  and  from  these  bodies  there  arose  occasionally  long, 
thin,  hyaline  filaments  which  possessed  the  property  of  motion.  This  form 
was  undoubtedly  the  flagellate  form  of  the  plasmodium.  The  third  form 
described  by  him  consisted  of  spherical,  slightly  granular  bodies,  with  motion- 
less pigment,  which  were  evidently  degenerative  forms  of  the  two  foregoing 
classes. 

Richard,  a  French  army  surgeon  serving  atPhilippeville,  Algeria,  confirmed 
Laveran's  discovery,  and  recognized  the  young,  hyaline,  intracorpuscular 
Plasmodia,  but  for  over  four  years  Laveran's  plasmodium  was  regarded  with 
but  little  scientific  interest,  the  bacillus  of  Klebs  and  Tommassi-Crudeli  being 
believed  to  be  the  true  cause  of  the  malarial  fevers.  However,  in  1885,  Marchi- 
afava  and  Celli  described  carefully  the  hyaline  intracorpuscular  parasites  and 
proposed  the  name  u Plasmodium  malaria;"  for  the  organisms.  In  the  same 
year,  Golgi  proved  that  quartan  malaria  depended  upon  a  specific  form  of  the 
plasmodium,  and  shortly  afterward  he  demonstrated  and  described  the  parasite 
causing  tertian  fever.  He  also  called  attention  to  the  probably  distinct  type  of  the 
crescentic  and  ovoid  forms  of  the  plasmodium,  and  to  him  we  owe  the  discovery 
that  the  malarial  paroxysm  always  coincides  with  the  segmentation  or  sporula- 
tion  of  a  group  of  parasites.  Occurring  every  forty-eight  hours,  the  segmenta- 
tion causes  a  tertian  fever,  while  if  it  occurs  every  seventy-two  hours  a 
quartan  fever  results.  Marchiafava  and  Celli  had  been  strong  supporters  of 
the  bacterial  causation  of  the  malarial  fevers,  and  when,  in  1885,  these  authors 
admitted  that  they  were  mistaken,  and,  although  they  had  previously  regarded 
Laveran's  parasites  as  degenerative  changes  in  the  red  blood-corpuscles, 
became  enthusiastic  advocates  of  their  parasitic  nature,  their  descriptions  of 
the  plasmodia  attracted  wide  attention,  and  were  soon  confirmed  by  numerous 
observers,  as  Councilman  and  Abbot,  Sternberg,  Osier,  Dock,  Grassi  and 
Feletti,  Antolisei,  Bastianelli  and  Bignami,  Mannaberg,  and  many  others. 
During  this  period  the  morphological  structure  of  the  plasmodia  was  carefully 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  7 

studied,  and  from  this  study  of  the  morphology  of  the  plasmodia  there  arose 
two  distinct  schools,  one  believing  in  the  unity  of  all  forms  of  the  plasmodia, 
the  other  believing  that  the  plasmodia  of  malaria  are  divided  into  distinct 
species.  The  first  school,  represented  by  Laveran,  believes  that  the  malarial 
Plasmodium  is  a  single  organism  occurring  in  many  forms;  while  the  second 
school  believes  that  there  are  several  species  of  plasmodia,  each  producing  its 
characteristic  type  of  fever,  and  each  easily  distinguished  by  differences  in 
morphology  and  in  its  life  cycle. 

The  minute  study  of  the  plasmodia  resulted  in  the  description  of  the  life 
cycle  of  all  the  species,  and  the  demonstration  of  the  occurrence  in  the  blood  of 
certain  forms,  spherical,  ovoid,  and  crescentic  in  shape,  that  did  not  sporulate, 
but  under  favorable  conditions  became  flagellated,  the  nature  of  which  was 
vainly  guessed  at  until  it  was  shown  that  these  forms  were  intended  to  continue 
the  life  of  the  plasmodia  outside  of  the  human  body.  Although  by  Laveran's 
great  discovery  the  diagnosis  of  malaria  was  placed  upon  a  scientific  basis, 
but  little  was  known  regarding  the  means  of  transmission  of  the  plasmodia; 
while  Gerhardt,  Mariotti,  Marchiafava,  Celli,  Bignami,  Bastianelli,  Baccelli, 
Sacharov,  Elting,  and  others  had  proved  that  the  malaria  fevers  may  be  trans- 
mitted by  direct  inoculation  from  man  to  man,  and  that  the  type  of  paraseti 
injected  is  found  again  in  the  blood  of  the  inoculated  individual,  yet  until  the 
researches  of  Ross  we  possessed  no  definite  knowledge  of  how  infection  occurred 
in  nature  or  of  the  life  cycle  of  the  plasmodia  outside  of  the  human  body. 

Fourth  Period.— To  the  brilliant  work  of  Ross,  Bignami,  Bastianelli, 
and  Grassi  the  world  is  indebted  from  the  elucidation  of  the  method  of  trans- 
mission of  the  malarial  fevers.  That  malaria  may  be  transmitted  by  insects 
is  by  no  means  a  modern  conception,  for  Varro  and  Columella  both  suggested 
that  these  fevers  might  be  transmitted  in  this  way,  while  Lancisi  mentioned 
the  mosquito  as  an  agent  in  the  spread  of  the  disease.  In  more  modern  times 
Nott  (1848)  considered  this  method  of  transmission  as  already  proven,  and 
King  (1882)  advocated  the  same  method  of  transmission  and  adduced  some 
evidence  in  its  support.  In  the  Goulstonian  lectures  of  1894,  Manson  elabo- 
rated the  theory  of  mosquito  transmission,  awakening  renewed  interest  in 
this  phase  of  the  study  of  malaria.  In  1895,  Ross  of  the  Indian  Army  Medical 
Service  studied  the  changes  occurring  in  the  aestivo-autumnal  plasmodia 
within  certain  species  of  mosquitoes,  and  in  1897  observed  the  encysted  forms 
of  these  plasmodia  within  the  stomach  wall  of  mosquitoes  of  the  genus 
Anopheles.  Ross  continued  his  observations  upon  birds  infected  with 
Halteridium,  the  parasite  of  avian  malaria,  demonstrating  that  in  Culex 
fatigans  which  have  bitten  infected  birds,  the  parasites  become  encysted  in 
the  stomach  wall,  and  undergo  a  series  of  developmental  changes  resulting  in 
the  formation  of  multitudes  of  sporozoites  which  accumulate  in  the  cells  of 
the  salivary  glands  and  reinfect  susceptible  birds  when  the  insect  bites.  Mac- 
Callum,  in  1898,  studying  the  same  parasite,  observed  that  two  forms  of  the 
fully  developed  halteridium  occurred  in  the  infected  birds,  one  of  which  is 


8  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

flagellated  and  the  other  nun-flagellated.  He  observed  that  the  llagella> 
breaking  away  from  the  flagellated  form,  penetrated  the  non-flagellated  organ- 
isms, and  after  penetration  a  motile  body  resulted  which  moved  about  among 
the  blood-corpuscles.  Later  he  observed  the  same  phenomena  in  studying 
the  aestivo-autumnal  parasites,  and  considered  that  this  process  was  one  of 
fertilization.  MacCallum's  researches  have  been  confirmed  by  Bastianelli, 
Bignami,  and  Grassi,  who,  working  with  the  parasites  of  human  malaria  and 
with  mosquitoes  of  the  genus  Anopheles,  have  demonstrated  that  fertilization 
occurs  in  the  stomach  of  the  mosquito  and  is  followed  by  encystment  in  the 
stomach  wall.  Their  observations  proved  that  the  plasmodia  undergo  the 
same  developmental  cycle  in  anopheles  mosquitoes  that  the  halteridium  undergoes 
in  Cnlex  fatigans. 

In  1898,  Bignami  was  successful  in  producing  an  attack  of  aestivo-autumnal 
malaria  in  man  by  allowing  mosquitoes  which  had  bitten  an  infected  individual 
to  bite  a  patient  who  had  never  had  malaria.  In  the  same  year,  Bastianelli, 
Bignami,  and  Grassi  were  successful  in  producing  a  double  tertian  infection  in 
man  by  the  bites  of  infected  Anopheles.  In  February,  1899,  they  were  for  the 
first  time  successful  in  infecting  Anopheles  maciilipennis  with  quartan  parasites, 
and  traced  the  developmental  stages  of  this  organism  in  the  mosquito.  They 
were  also  successful  in  producing  aestivo-autumnal  malaria  by  the  bites  of 
infected  mosquitoes.  These  results  have  been  confirmed  by  numerous  ob- 
servers and  prove  beyond  question  that  the  malarial  fevers  are  transmitted 
by  mosquitoes  and  that  there  are  at  least  three  species  of  malarial  plasmodia. 

Geographical  Distribution. — The  malarial  fevers  are  world-wide  in 
their  distribution,  but  certain  localities  are  entirely  free  from  malarial  infection. 
In  the  Eastern  hemisphere  such  infections  are  rare  above  620  N.  Latitude, 
while  in  the  Western  hemisphere  they  are  but  rarely  found  above  450  N.  Lati- 
tude. They  are  most  common  and  most  severe  in  low-lying  coast  regions, 
mountainous  countries  being  comparatively  exempt.  The  deltas  of  large 
rivers,  especially  the  rivers  of  tropical  countries,  are  hot-beds  of  malarial 
disease,  and  this  is  also  true  of  all  bodies  of  water  situated  in  such  localities. 
As  we  approach  the  equator  we  meet  less  often  with  the  benign  forms  of  malarial 
infection,  the  prevailing  types  being  the  severe  and  often  fatal  aestivo-autumnal 
infections. 

While  the  aestivo-autumnal  fevers  are  thus  more  strictly  bounded  as 
regards  distribution  than  are  either  the  tertian  or  the  quartan  forms  of  malaria, 
they  are  yet  so  widely  spread  as  to  make  their  recognition  of  the  first  importance 
to  American  practitioners,  for  they  not  only  occur  in  the  semi-tropical  regions 
of  the  United  States,  but  are  very  prevalent  in  our  colonial  possessions,  such  as 
the  Philippine  Islands  and  Porto  Rico  and  along  the  line  of  the  Panama  Canal. 
In  these  regions  the  aestivo-autumnal  fevers  are  endemic,  and  have  proven  to  be 
the  greatest  obstacle  to  colonization  by  the  white  race.  Malaria  is  a  greater  foe 
to  civilization  in  the  tropics  than  is  any  other  one  factor,  and  Koch  justly  says: 
"Malaria  is  met  with  everywhere;  the  officer  in  his  bureau,  the  traveler  in  the 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  9 

interior,  the  soldier  upon  the  march,  all  must  recognize  that  soon  or  late  they  are 
to  become  the  victims  of  malaria." 

The  distribution  of  the  malarial  fevers  depends  upon  the  presence  of 
mosquitoes  belonging  to  the  Anophelina:;  the  presence  of  infected  individuals; 
proper  climatic  conditions  as  to  temperature  and  moisture;  and  susceptibility 
of  the  individual  bitten  by  infected  mosquitoes  to  malaria.  Unless  all  of  these 
factors  be  present  the  malarial  fevers  will  not  be  found  except  as  imported 
cases,  and  the  country  so  fortunate  as  to  be  thus  unsuitable  to  the  propagation  of 
malaria  will  remain  free  from  the  disease.  The  presence  of  species  of  the 
Anophelinse  does  not  presuppose  the  existence  of  malaria,  as  some  of  the 
Anophelina?  are  incapable  of  transmitting  malaria,  while  even  in  localities 
where  the  right  species  are  present  no  malaria  will  be  found  unless  an  infected 
individual  has  entered  the  district  and  infects  the  mosquitoes. 

Given  all  of  the  factors  mentioned,  the  malarial  fevers  may  be  endemic  in 
certain  regions,  or  may  become  epidemic  in  regions  ordinarily  free  from  such 
infections.  Extensive  pandemics  of  malaria  are  described  by  many  writers, 
one  of  which,  in  1558,  covered  all  of  Europe,  while  many  epidemics  have 
occurred,  the  last  between  1866  and  1872,  spreading  over  much  of  Europe  and 
a  large  portion  of  India  and  North  America.  Local  epidemics  of  malaria  are 
often  observed  in  places  which  may  have  been  free  from  infection  for  many 
years.  An  instance  of  this  kind  occurred  under  my  observation  in  a  city  in 
Connecticut.  Some  years  before  the  Spanish-American  War  this  city  occasion- 
ally reported  the  presence  of  tertian  malarial  fever,  but  the  cases  were  few  in 
number  and  no  other  form  of  malaria  was  ever  observed.  After  the  return  of  a 
company  of  militia  at  the  close  of  the  war  mentioned,  several  cases  of  remittent 
fever  were  observed  which  upon  investigation  were  found  to  be  infections  with 
the  aestivo-autumnal  malarial  plasmodia.  The  introduction  of  this  organism 
was  traced  to  the  returning  soldiers,  some  of  whom  had  suffered  from  this  form 
of  malaria  while  in  Cuba  upon  special  service.  In  this  instance  the  conditions 
necessary  for  the  spread  of  the  disease  were  all  present  in  the  city  with  the 
exception  of  the  infected  individuals;  the  right  species  of  Anopheles,  warmth  and 
moisture,  and  a  susceptible  people,  awaited  only  the  returning  soldier  infected 
with  the  aestivo-autumnal  plasmodium,  and  thus  a  form  of  malaria  never  before 
observed  in  the  State  of  Connecticut  became  prevalent  in  this  city.  Such 
instances  could  be  multiplied  and  well  illustrate  the  facility  with  which  malaria 
may  be  introdcued  into  localities  previously  free  from  these  fevers. 

The  most  important  places  in  which  malaria  is  endemic  are  the  following: 

North  America. — In  North  America  malaria  occurs  rarely  above  the 
forty-fifth  parallel.  Along  the  entire  Atlantic  coast  line  these  fevers  are  ob- 
served, the  New  England  States  showing  the  fewest  and  the  mildest  cases,  the 
disease  increasing  in  severity  as  the  Southern  States  are  reached,  where  the 
aestivo-autumnal  fevers  not  infrequently  result  fatally.  The  most  severe  forms 
prevail  along  the  low  regions  of  the  southern  coast  line,  and  especially  in  the 
swamps  of  the  Gulf  States.     Texas,  Georgia,  and  Florida  are  badly  infected 


IO  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

in  some  portions  with  aestivo-autumnal  malaria;  this  form  is  also  common 
along  the  southern  portion  of  the  Mississippi  and  its  tributaries  and  there  are 
regions  in  the  delta  of  the  Mississippi  that  are  uninhabitable  because  of  the 
prevalence  of  the  most  deadly  forms  of  aestivo-autumnal  infection.  Along  the 
Missouri  and  Arkansas  Rivers  the  malarial  fevers  are  very  prevalent,  and  the 
disease  is  common  in  the  States  of  Mississippi,  Missouri,  Arkansas,  Kansas, 
Oklahoma,  and  certain  parts  of  New  Mexico.  The  States  of  North  and  South 
Carolina,  Virginia,  Maryland,  and  West  Virginia  are  all  infected,  but  to  a  less 
extent.  Ohio,  Indiana,  Illinois,  Michigan,  Minnesota  and  Wisconsin  are 
infected  with  the  benign  tertian  type  of  malaria,  but  only  in  limited  localities, 
and  to  a  much  smaller  extent  than  are  the  Southern  States.  Of  the  Western 
States,  Wyoming,  Utah,  Arizona,  and  California  are  more  or  less  malarial,  and 
in  the  valleys  of  the  Sacramento  and  San  Joaquin  in  California,  pernicious 
forms  of  aestivo-autumnal  malaria  are  not  uncommon,  while  the  benign  tertian 
infections  are  very  prevalent.  The  regions  about  the  Great  Lakes  are  almost 
free  from  malaria  except  in  certain  localities  about  Lake  Michigan  and  Lake 
Ontario,  while  Canada  appears  to  be  free  from  these  fevers  except  in  the  most 
Southern  portions  bordering  upon  the  Great  Lakes,  and  the  infections  are  all 
of  mild  character. 

Almost  all  of  the  islands  of  the  West  Indies  are  badly  infected  with  the 
malarial  fevers,  especially  Cuba,  where  aestivo-autumnal  malaria  is  most 
prevalent  and  fatal  in  character.  Barbados  and  St.  Vincent  are  said  to  be  free 
from  malaria,  and  in  Porto  Rico  the  benign  intermittents  are  the  most  common 
forms  observed. 

Mexico  and  Central  America  are  hot-beds  of  the  most  deadly  forms  of 
aetsivo-autumnal  infection,  and  the  low-lying  coast  lines  of  these  countries  are 
among  the  most  dangerous  of  the  lurking  places  of  this  form  of  disease.  The 
dreaded  Chagres  fever  of  Panama  is  a  form  of  aestivo-autumnal  infection,  and, 
together  with  yellow  fever,  compelled  the  French  to  abandon  the  digging  of  the 
Panama  Canal. 

In  South  America  malarial  infections  are  common  in  the  northern  part  of 
Brazil,  in  Uruguay,  Paraguay,  Bolivia,  Venezuela,  Guiana,  and  Colombia.  The 
Argentine  Republic,  Peru,  and  Ecuador  suffer  less  from  malaria,  but  all  are 
infected. 

Europe. — Great  Britain  may  be  said  to  be  entirely  free  from  malarial 
infection,  imported  cases  being  the  only  ones  observed  in  that  country.  In 
Germany,  malarial  infections  occur  along  the  coast  of  the  Baltic,  and  they  are 
not  uncommon  in  the  swamps  of  Hanover  and  Westphalia,  and  along  the 
Rhine  and  its  tributaries.  In  Holland  and  Belgium  malaria  is  endemic  in  the 
river  bottoms  and  in  marshy  regions.  In  France  these  infections  occur  along 
the  Loire  and  Rhone,  the  West  Coast,  the  river  Brenne,  and  the  Sologne.  In 
these  regions  only  the  benign  forms  are  observed,  and  this  is  also  true  of  the 
malaria  of  Germany. 

In  Spain  the  valleys  of  the  Tago  and  the  Quadalquivir  are  infected,  and 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  II 

pernicious  forms  occur  in  all  the  countries  bordering  upon  the  Mediterranean; 
in  Greece,  Crete,  Italy,  Sicily,  and  Turkey,  aestivo-autumnal  infections  are 
common,  as  are  also  the  tertian  and  quartan  fevers;  in  Italy,  especially,  occur 
the  most  malignant  forms  in  the  regions  around  the  Roman  Campagna  and 
the  Pontine  marshes,  as  well  as  in  the  valley  of  the  Po  and  along  the  entire 
West  Coast.  Sardinia  and  Corsica  are  also  infected  with  the  pernicious  forms 
of  aestivo-autumnal  malaria.  In  Austria-Hungary  malarial  infections  are 
present  in  Galicia,  in  the  valley  of  the  Danube,  and  along  the  Adriatic.  In 
Turkey  severe  infections  occur  along  the  Danube;  in  Russia  malarial  infections 
are  prevalent  in  the  valleys  of  the  Volga,  Dniester,  and  Dnieper,  and  they  are 
also  common  along  the  coast  lines  of  the  Black  and  Caspian  Seas  and  the  Sea 
of  Azov. 

Asia. — Asia  Minor,  Persia,  Arabia,  India,  and  Ceylon,  as  well  as  portions 
of  China  and  nearly  all  of  the  islands  of  the  Malay  Archipelago  are  infected 
with  the  malarial  fevers.  The  valleys  of  all  of  the  great  rivers,  such  as  the 
Indus  and  the  Ganges,  are  heavily  infected,  and  pernicious  forms  are  common; 
even  upon  the  lofty  tablelands  of  the  Himalayas  malarial  infections  are  often 
met  with,  and  the  region  of  jungle  country  known  as  the  Terai,  at  the  foot  of 
the  Himalayas,  is  considered  one  of  the  most  dangerous  of  malarial  districts. 
Java  and  Sumatra  are  badly  infected  with  malaria,  as  are  certain  parts  of 
Borneo.  The  Philippine  Islands,  until  quite  recently  considered  as  being 
comparatively  free  from  malaria,  have  been  proved  to  be  badly  infected,  the 
islands  of  Luzon,  Samar,  Mindoro,  and  Mindanao  showing  infection  with  all 
the  species  of  malarial  plasmodia.  In  the  island  of  Luzon,  the  foot  hills  of  the 
Zambales  Mountains  and  the  part  of  the  great  Pampangan  Plain  in  the  region 
of  the  foot  hills,  are  infected  with  the  most  pernicious  forms  of  aestivo-autumnal 
malaria,  while  there  are  certain  regions  in  the  islands  of  Samar  and  Mindoro 
that  are  shunned  by  the  natives  on  account  of  the  deadly  malarial  infections 
which  are  present. 

Africa. — In  Africa  are  some  of  the  most  dangerous  lurking  places  of 
malarial  infections,  the  worst  areas  being  those  along  the  West  Coast,  and  the 
valleys  of  the  Senegal,  Congo,  and  Niger  rivers,  as  well  as  the  regions  around 
the  great  lakes  and  the  jungles  and  lake  shores  of  Abyssinia.  In  Egypt  the 
only  infected  districts  are  situated  in  the  delta  of  the  Nile;  Tunis,  Tripoli, 
Algiers,  the  oases  of  the  Sahara,  and  the  East  Coast  are  infected  with  all  forms 
of  the  malarial  plasmodia,  but  aestivo-autumnal  infections  are  most  common. 
The  islands  of  St.  Helena,  the  Seychelles,  and  Rodriguez  are  free  from  malaria, 
and  the  same  is  true  of  Cape  Colony,  the  Orange  Free  State,  and  of  German 
Southwest  Africa.  Madagascar,  Mauritius,  and  Reunion  are  infected  with 
malaria,  pernicious  forms  occurring  in  all  of  these  islands.  The  continent  of 
Australia  is  free  from  malaria,  as  are  most  of  the  islands  of  Polynesia. 

The  resume  given  indicates  the  most  important  regions  in  which  the 
malarial  fevers  are  endemic,  but  there  are  numerous  districts  in  which  a  few 
sporadic  cases  occur  at  rare  intervals,  but  which  at  any  time  may  become 


12  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

endemic  foci,  provided  certain  species  of  the  Anophelinre  are  present,  together 
with  individuals  harboring  the  malarial  plasmodia.  In  our  own  country  the 
return  of  hundreds  of  our  soldiers  from  the  Philippine  Islands  infected  with  the 
various  forms  of  malaria  so  prevalent  there,  especially  the  aestivo-autumnal, 
will  inevitably  result  in  the  infection  of  localities  hitherto  free  from  malarial 
disease,  and  unless  these  infections  be  promptly  recognized,  such  localities 
will  become  endemic  foci  of  the  malarial  fevers. 

A  knowledge  of  the  geographical  distribution  of  these  fevers  is  of  much 
practical  value,  as  localities  known  to  be  infected  can  thus  be  avoided,  and 
those  who  travel  through  them,  or  reside  within  them,  can  take  the  proper 
precautions  to  prevent  infection.  A  knowledge  of  the  distribution  of  these 
fevers  is  also  of  great  assistance  in  the  diagnosis  of  unusual  or  obscure  forms  of 
fever  and  in  the  prophylaxis  of  malaria.  The  blood  of  every  patient  coming 
from  a  malarial  region  should  be  examined,  and  if  the  plasmodia  are  found, 
quinin  should  be  administered  and  the  proper  measures  taken  to  protect  the 
community  from  the  infection. 

Monographs  upon  the  Malarial  Fevers. 

1889.  Kelsch  and  Kiener.      Traite  des  maladies  des  pays  chauds.      Paris. 

1890.  Schellong.      Die  Malariakrankheiten,  etc.      Berlin. 

1895.  Thayer  and  He wetson.     The  Malarial  Fevers  of  Baltimore.      Baltimore. 

1895.  Baccelli.      Studien  uber  Malaria.      Berlin. 

1896.  Rho.      La  Malaria.      Torino. 

1897.  Thayer.      Lectures  upon  the  Malarial  Fevers.      New  York. 

1898.  Laveran.      Traite  du  paludisme.      Paris. 

1898.  Zieman,  H.      Ueber  Malaria  und  andere  Blutparasiten.      Jena. 

1899.  Mannaberg.      Die   Malaria   Krankheiten.       Nothnagel's   Encyclopaedia. 
Berlin. 

iqoo.      Celli.      Malaria.      London. 

1900.  Marchiafava    and    Bignami.      Malaria.      Twentieth   Century   Practice. 
New  York. 

1 90 1.  Grassi.      Die  Malaria:      Studien  eines  Zoologen.      Jena. 
1901.      Neveu-Lemaire.      Les  hematozoaires  du  paludisme.      Paris. 

1901.      Ruge,  R.      Einfiihrung  in  das  Studium  der  Malariakrankheiten.      Jena. 
1 90 1.     Craig,  C.  F.     The  Aestivo-autumnal  (Remittent)  Malarial  Fevers.      New 

York. 
1904.      Stephens  and  Christophers.     Practical    Study  of  Malaria  and  other 

Blood  Parasites.      London. 

1906.  Zieman,      H.      Malaria.      Handbuch     der      Tropenkrankheiten.      Mense. 
Leipzig. 

1907.  Thayer.     Malaria.     System  of  Medicine,  Albutt  and  Rolleston.     London. 
1907.      Craig,  C.  F.      The  Malarial  Fevers.      Modern  Medicine.      Osier.      Phila- 
delphia. 

Historical  Literature. 

Hippocrates.      The  Genuine  Works  of  Hippocrates.      Adams  Trans.      New  York. 
Celsus.      De  Medicina,  libri  viii. 
Varro.      "Rerum  Rusticarum,"  Lib.  i 
Columella.     "  De  re  Rustica,"  Lib.  i,  Cap.  5. 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  1 3 

Palladius.      "Dere  Rustica,"  Lib,  i,  Cap.  7. 

1697.      Morton.      "  Opera  Omnia.  "  Lugduni. 

1717.      Lancisi.      De  noxiis  paludum  effluviis.      Rome. 

1723.     Sydenham.     "Opera  Medica. "     Genevae. 

1743.      Torti.      Therapeuticae  specialis  ad  febres  quasdam  perniciosas.      Editio 

quarta.      Venetiis. 
1847.      Meckel.      Ueber  schwarzes  Pigment    in    der    Milz    und    im    Blut   einer 

Geisteskranken.      Zeitschr.  f.  Psychiatric,  S.  198. 
1894.      Virchow.    Zur  pathologischen  Physiologie  des  Blutes.      Virch     Archiv, 

ii,  587- 
1849.      Mitchell.      On  the  Cryptogamous   Origin  of  Malarious  and   Epidemic 

Fevers.      Philadelphia. 
1866.      Salisbury.      Amer.  Jour.  Med.  Sciences,  January. 
1870.      Colin.      Traite  des  fievres  intermittentes.      Paris. 

1879.  Klebs  and  Tomassi-Crudeli.  Studien  uber  Ursache  des  Wechsel- 
fiebers  und  uber  die  Natur  der  Malaria.  Arch.  f.  exp.  Path.  u.  Pharmak., 
xi,  311. 

1880.  Tomassi-Crudeli.  Studi  ulteriori  sul  Bacillus  malarue.  Bull,  dell 
R'  accad,  med.  di  Roma,  vi,  9-12. 

1880.     Tomassi-Crudeli.     Malarial  Fever.     The  Practitioner,  Nov.,  xxv,  320. 

Laveran.      Note  sur  un  nouveau  parasite,  etc.      Bull,  de  l'acad.  de  med. 

de  Paris,  se.  du  23  Nov. 

Laveran.      C.  R.  Acad.  Sc.  Paris.  T.  xciii,  p.  627. 

Fayrer.      On  the  Climate  and  Fevers  of  India.      London. 

Richard.      Sur  le  parasite  de  la  malaria.      Compt.  rend,  des  l'acad.  des 

sciences,  Paris,  se.  20  Febr. 

Richard.      Le  parasite  de  rimpaludisme.      Rev.   Scientifique,   Paris,   p. 

113- 

Marchiafava  and  Celli.      Die  Veranderungen  der  rothen  Blutscheiben 

bei  Malariakranken.      Fortschritte  der  Med.,  Leipzig,  i,  573. 

Marchiafava   and   Celli.      Weitere  Untersuchungen  uber  die   Malaria 

infection.     Fortschritte  der  Med,  iii,  No  24,  787. 

Golgi.      Sulla  infezione  malarica.      Gaz.  degli  Osp.,  No.  53,  419. 

Councilman  and  Abbott.      A  Contribution  to  the  Pathology  of  Malarial 

Fever.  Am.  Jour.  Med.  Sci.,  Apr.,  vol.  89,  416. 

Osler.      An  Address  on  the   Hematozoa  of  Malaria.    Brit.    Med.  Jour., 

i>  556. 

Sternberg.      The  Malarial  Germ  of  Laveran.      Med.  Record,  May  1  and 

8,  489. 

1886.  Councilman.  On  Certain  Flements  Found  in  the  Blood  in  Cases  of 
Malarial  Fever.      Trans.  Assoc.  Amer.  Phys.,  i,  90. 

1887.  Councilman.  Further  Observations  on  the  Blood  in  Cases  of  Malarial 
Fever.  Med.  News,  i,  59-63. 

Sacharoff.      Untersuchungen   uber   den   Parasiten    des    Malariafiebers. 
Protocols  of  the  Caucassian  Med.  Soc,  at  Tiflis,  No.  6,  147. 

17.      Ross,   R.      On  Some  Peculiar  Pigmented  Cells  Found  in  Two  Mosquitoes 
fed  on  Malarial  Blood.      Brit.  Med.  Jour.,  vol.  ii,  p.  1786. 
Ross,    R.      The  Role  of  the  Mosquito  in  the  Evolution  of  the  Malarial 
Parasite.      The  Lancet,  vol.  ii,  p.  488. 
Grassi,  B.,  Bastianelli,  G.,  et  Bignami,  A.      Contributions  as  follows 

1898.  Rend,  della  R.  Accad  dei  Lincei,  vol.  vii,  Series  5a. 

1899.  Ibid.,  vol.  viii,  Series,  5a,  p.  434. 

1899.      Atti  Soc.  per  gli  studi  della  malaria,  vol.  i,  p.  14. 


CHAPTER  II. 

Etiology ;     Classification  ot  the  Parasites  of  the  Malarial  Fevers ;     Morphology 
and  Biology  of  the  Malarial  Plasmodia  in  the  Blood  of  Man. 

Classification  of  the  Malarial  Parasites. — From  the  time  of  the  discovery 
by  Laveran  of  the  malarial  plasmodia  to  the  present,  much  attention  has  been 
devoted  by  zoologists  to  the  proper  classification  of  these  organisms,  and  many 
different  opinions  have  been  advanced  concerning  their  exact  zoological  posi- 
tion. Laveran  proposed  the  name  "Oscillaria  malaria"  for  the  parasite, 
but  later  accepted  Osier's  name  of  "  Haematozoon. "  In  1887,  Metchnikoff 
placed  the  organisms  among  the  Sporozoa,  and  proposed  the  name  "  Haema- 
tophyllum  malaria"  for  the  malarial  parasite  of  man.  To  Danilewsky  we 
owe  the  new  division  of  the  Sporozoa  into  a  group  known  as  the  Haemosporidia 
in  which  he  placed  the  malarial  plasmodia.  The  genus  " Plasmodium" 
was  created  by  Marchiafava  and  Celli,  and  all  the  plasmodia  of  man  placed 
in  this  genus  by  these  authors.  At  the  present  time,  then,  it  is  conceded  by  all 
zoologists  that  the  parasites  causing  the  malarial  fevers  belong  to  the  Protozoa; 
order  Sporozoa;  sub-order  Haemosporidia,  and  genus  Plasmodium. 

The  existence  of  distinct  species  of  plasmodia  associated  with  equally 
distinct  types  of  malarial  fever  has  been  abundantly  demonstrated  by  many 
careful  observers,  and  the  work  of  Marchiafava  and  Bignami,  Celli,  Grassi, 
Golgi,  and  others  has  resulted  in  the  separation  of  at  least  three  species  of 
Plasmodium,  differing  in  their  morphology  and  life  history  as  well  as  in  the 
effects  they  produce  in  man  when  blood  containing  them  is  inoculated  or 
when  infected  mosquitoes  are  allowed  to  bite  susceptible  individuals. 

Laveran  and  his  followers  believe  that  the  parasite  producing  malarial 
fever  is  a  polymorphous  organism,  assuming  very  great  differences  in  morph- 
ology under  differing  conditions  of  environment,  and  that,  in  Laveran's  words, 
"there  does  not  exist  a  constant  relation  between  the  forms  under  which  the 
haematozoa  appear  in  the  blood  and  the  clinical  manifestations  of  paludism; 
one  can  only  say  that  certain  forms  of  the  parasite  are  more  often  seen  in  certain 
cases,  the  crescents,  for  instance,  in  relapses  and  in  malarial  cachexia."  Some 
of  Laveran's  followers  even  claim  to  have  observed  interchangeability  of  the 
various  species  which  have  been  described,  but  their  observations  still  await 
confirmation,  and  the  great  weight  of  evidence  to-day,  both  morphological  and 
experimental,  is  in  favor  of  the  existence  of  several  species  of  malarial  plasmodia. 
The  existence  of  at  least  three  species  of  plasmodium,  the  tertian,  quartan,  and 
aestivo-autumnal,  has  been  accepted  by  every  investigator  in  America,  England, 

14 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  1 5 

Germany,  Italy,  and  in  tropical  regions,  as  India  and  Africa,  but  considerable 
uncertainty  exists  as  to  the  species  concerned  in  the  production  of  the  various 
forms  of  aestivo-autumnal  infection.  The  Italian  authorities,  together  with 
nearly  every  investigator  who  has  studied  malaria  in  the  tropics,  have  made 
a  subdivision  of  the  aestivo-autumnal  parasite  into  at  least  two  varieties,  the 
quotidian  and  the  tertian,  and  a  great  amount  of  labor  has  been  expended  in 
differentiating  these  varieties  and  in  endeavoring  to  demonstrate  their  specific 
characteristics.  From  personal  experience  I  have  no  hesitation  in  stating  that 
the  tertian  and  quotidian  aestivo-autumnal  plasmodia  can  be  as  easily  differen- 
tiated as  the  benign  tertian  and  quartan  plasmodia,  when  suitable  material 
is  available  for  study,  and  while  I  cannot  accept  the  existence  of  a  pigmented 
and  unpigmented  quotidian  aestivo-autumnal  parasite,  I  believe  that  the 
aestivo-autumnal  infections  are  produced  by  two  distinct  organisms,  the 
quotidian  and  the  tertian  aestivo-autumnal  plasmodium. 

Several  of  the  classifications  proposed  for  the  parasites  of  malaria  are  of 
interest  and  will  be  briefly  noticed. 

Labbe's  Classification. — Labbe  placed  all  of  the  blood  parasites  belong- 
ing to  the  Protozoa  in  the  Sporozoa,  dividing  them  into  two  classes:  Haemo- 
sporidia  and  Gymnasporidia,  in  the  latter  division  placing  the  malarial  parasites 
of  man  as  well  as  the  HaUeridium  and  Proteosoma  of  birds. 

Kruse's  Classification. — Kruse  divides  the  Sporozoa  into  four  orders, 
placing  the  malarial  parasites  in  the  Gregarinida,  sub-order  Haemogregarinidcz; 
genus  Plasmodium,  the  generic  term  first  given  by  Marchiafava  and  Celli. 

Grassi  and  Feletti's  Classification. — These  authors  placed  all  of  the 
malarial  parasites  in  two  genera:  Haemamoeba  and  Laverania.  In  the  genus 
Haemamoeba,  they  mention  four  species  of  malarial  parasites  as  occurring 
in  man:  H.  malaria  (quartan),  H.  vivax.  (tertian),  H.  praecox.  (pernicious), 
and  H.  immaculata  (pernicious).  In  the  genus  Laverania,  they  place  the 
crescentic  parasites,  giving  them  the  specific  name  "Laverania  malarice." 
Neither  the  generic  or  specific  name  in  this  instance  can  stand,  as  both  were 
founded  upon  the  belief  that  the  crescents  were  a  distinct  species  of  parasite. 

Mannaberg's  Classification. — Mannaberg  divides  the  malarial  para- 
sites as  follows: 

i.  Malarial  parasites  that  sporulate,  but  do  not  form  syzygies  (crescents). 

a.  Quartan  plasmodium. 

b.  Tertian  plasmodium. 

2.  Malarial  parasites  that  sporulate  and  form  syzygies  (crescents). 

a.  Pigmented  quotidian  plasmodium. 

b.  Non-pigmented  quotidian  plasmodium. 

c.  Malignant  tertian  plasmodium. 

Thayer  and  Hewetson's  Classification. — In  their  classical  work  upon 
the  malarial  fevers  Thayer  and  Hewetson  divide  the  parasites  of  malaria  into 
three  species,  the  tertian,  quartan  and  aestivo-autumnal  parasites. 

Sacharoff's  Classification. — Sacharoff  divides  the  plasmodia  into  two 


1 6  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

genera,  Hacmamoebcc  and Laverania;  in  the  first  genus  he  includes  three  species, 
as  follows: 

Hacmamocba  praccox  (aestivo-autumnal).     Grassi. 
Haemamocba  febris  lertianae  (tertian).     Golgi. 
Haemamoeba  febris  quartanae  (quartan).     Golgi. 
In  the  second  genus,  Laverania,  he  includes  one  species,  characterized  by  a 
crescentic  shape.     In  this  Sacharoff  followed  Grassi  and  Feletti,  believing  that 
the  crescents  were  a  distinct  species  of  parasite. 

Zieman's  Classification. — Zieman  divides  the  malarial  plasmodia  into 
four  species,  the  tertian,  quartan,  pernicious  (aestivo-autumnal),  and  pernicious 
— varietas  Africana. 

Luhe's  Classification.— The  classification  of  Liihe,  accepted  by  many 
authorities,  divides  the  malarial  parasites  into  two  genera,  Laverania  and 
Plasmodium.  In  the  genus  Laverania  he  places  the  aestivo-autumnal  parasite, 
while  in  the  genus  Plasmodium  he  places  the  tertian  and  quartan  parasites,  as 
well  as  those  occurring  in  warm-blood  animals  other  than  man,  and  in  birds. 
According  to  Luhe,  the  three  parasites  of  man  should  be  thus  classified: 
Genus,  Laverania. 

Species,  Laverania  malar iae.     Gr.  et  Fe.     1890. 
Genus,  Plasmodium.     Marchiafava  and  Celli. 

Species,  Plasmodium  malaria:.  Marchia  et  Celli.     Quartan  parasite. 
Plasmodium  vivax.     Gr.  et  Fe.     Tertian  parasite. 
As  has  been  stated,  the  generic  name  "Laverania"  can  not  be  retained  and 
the  generic  name  "Plasmodium"  should  be  substituted  for  it. 

Scbaudinn's  Classification. — The  classification  of  the  parasites  of 
malaria  most  generally  accepted  by  zoologists  and  students  of  malaria  has  been 
that  of  Schaudinn,  who  divided  the  organisms  into  three  species  as  follows: 

1.  Plasmodium  vivax.     Gr.  et  Feletti.     Tertian  parasite. 

2.  Plasmodium  malariae.     Marchiaf  et  Celli.     Quartan  parasite. 

3.  Plasmodium  immacidatum.     Gr.  etFe.     Aestivo-autumnal  parasite. 
The  specific  name  "immaculatum"  can  no  longer  be  retained,  however,  for 

the  aestivo-autumnal  plasmodium,  for  Blanchard  has  shown  that  Grassi  pre- 
viously used  this  name  for  a  parasite  occurring  in  birds,  thus  preventing  its  use 
for  the  human  parasite.  This  fact  renders  the  specific  name  proposed  by 
Welch  "falciparum"  the  proper  name  for  the  aestivo-autumnal  plasmodium, 
and  Blanchard's  classification,  which  follows,  the  most  recent  and  generally 
accepted  of  the  many  which  have  been  mentioned. 

Blanchard's  Classification. — This  classification  divides  the  parasites 
of  malaria  into  three  species,  as  follows: 

1.  Plasmodium  malariae.     Marchiaf.  et  Celli.     Quartan  parasite 

2.  Plasmodium  vivax.     Gr.  et  Fe.  Tertian  parasite. 

3.  Plasmodium  falciparum.     Blanchard.     Aestivo-autumnal  parasite. 
While  almost  all  authorities  now  admit  the  existence  of  three  species  of 

malarial  plasmodia,  the  tertian,  quartan,  and  aestivo-autumnal,  the  question  of 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  1 7 

the  existence  of  more  than  one  species  of  the  latter  organism  is  still  an  undecided 
one.  By  many  authorities  the  aestivo-autumnal  plasmodia  are  divided  into 
two  varieties,  a  tertian  and  quotidian,  while  by  some  the  quotidian  is  subdivided 
into  a  pigmented  and  unpigmented  quotidian  parasite.  Other  authorities 
maintain  that  there  is  but  one  aestivo-autumnal  plasmodium,  the  variations 
observed  in  the  temperature  curve  being  due  to  variations  in  the  time  of  the 
developmental  cycle,  which  may  be  24  or  48  hours  in  length.  Personally,  as  J 
have  stated,  there  is  no  doubt  in  my  mind  that  the  two  varieties  of  this  parasite 
first  described  by  Marchiafava  and  Bignami,  tertian  and  quotidian,  are  distinct 
species  and  are  distinguishable  upon  both  morphological  and  clinical  grounds. 
I  have  arrived  at  this  conclusion  after  the  careful  study  of  the  plasmodia  found 
in  many  hundred  cases  of  aestivo-autumnal  fever  and  after  years  of  study  of 
malarial  infections  in  both  tropical  and  temperate  regions.  These  plasmodia 
can  be  differentiated  morphologically,  and  the  infections  produced  by  them  are, 
when  uncomplicated,  clinically  distinct.  Anyone  who  can  differentiate  the 
tertian  and  quartan  plasmodia  morphologically  should  have  no  trouble  in  dis- 
tinguishing between  the  tertian  and  quotidian  aestivo-autumnal  plasmodia  if 
blood  from  the  spleen,  obtained  by  puncture,  be  examined.  To  one  who  has 
had  the  opportunity  of  studying  a  large  number  of  aestivo-autumnal  infections 
the  two  parasites  can  be  readily  distinguished  by  the  forms  occurring  in  the 
peripheral  blood. 

The  argument  that  the  tertian  and  quotidian  temperatures  observed  in 
aestivo-autumnal  malaria  are  due  to  the  sporulation  of  a  parasite  which  at  one 
time  completes  its  developmental  cycle  in  the  human  body  in  24  hours  and  at 
another  time  in  48  hours  would  appear  to  be  illogical,  and  can  as  well  be  used  in 
the  case  of  the  tertian  and  quartan  plasmodia  by  those  who  still  maintain  that 
there  is  but  one  species  of  malarial  plasmodium. 

I  have  not  been  able  to  demonstrate  the  existence  of  a  pigmented  and  an 
unpigmented  quotidian  plasmodium  as  specifically  distinct  forms,  for  while  it 
is  not  uncommon  to  observe  only  unpigmented  quotidian  plasmodia  in  the 
peripheral  blood  upon  a  cursory  examination  in  aestivo-autumnal  infections, 
the  spleen  invariably  shows  pigmented  organisms,  and,  as  a  rule,  an  extended 
search  will  reveal  pigmented  organisms  in  the  peripheral  blood. 

In  view  of  the  division  of  the  aestivo-autumnal  plasmodia  into  two  species, 
I  would  suggest  the  following  classification  of  the  malarial  plasmodia: 

Division,  Protozoa. 

Class,  Sporozoa. 

Sub-class,  Telosporidia. 

Order,  Haemosporidia. 

Genus,  Plasmodium. 

Species    I. — Plasmodium   malariae.     Marchiaf.     et  Celli.     (Quartan 
malarial  parasite.) 
II. — Plasmodium  vivax.   Grassi  et  Feletti.    (Tertian  malarial 
parasite.) 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 


III. — Plasmodium  falciparum.     Blanchard.     (Tertian    aestivo- 

autumnal  parasite.) 
IV '. — Plasmodium  falciparum  quotidianum.  Craig.     (Quotidian 

aestivo-autumnal  parasite.) 


Morphology    and    Biology    of    the   Malarial    Plasmodia    in    the 

Blood    of   Man. 

General  Considerations. — The  malarial  plasmodia  are  found  in  man 
within  or  upon  the  red  blood-corpuscles  and  are  essentially  parasites  living 
at  the  expense  of  these  cells.  In  this  situation  they  destroy  the  red  corpuscles, 
producing  the  well-known  anaemia  peculiar  to  the  malarial  fevers,  together 
with  the  pigmentation,  or  melanaemia,  which  is  due  to  the  destruction  of  the 
haemoglobin  of  the  infected  cells.  Owing  to  the  researches  and  discoveries 
of  Ross,  Grassi,  Marchiafava,  Celli,  and  others,  it  is  now  necessary  in  describing 
the  malarial  plasmodia  to  consider  the  forms  present  in  two  life  cycles,  that 
within  man  and  that  within  mosquitoes  belonging  to  the  Anophelinas.  The 
life  cycle  completed  within  man,  the  intermediate  host,  is  known  as  the  endog- 
enous or  asexual  cycle,  and  the  growth  and  sporulation  of  the  parasites  is 
called  shizogony;  the  cycle  completed  within  the  mosquito,  or  definitive  host, 
is  known  as  the  exogenous,  or  sexual  cycle,  and  the  process  of  development  of 
the  parasites  as  sporogony.  In  this  chapter  will  be  considered  the  morphology 
and  biology  of  the  forms  of  the  malarial  plasmodia  concerned  in  schizogony, 
together  with  those  forms  concerned  in  sporogony  which  may  be  demonstrated 
in  the  blood  of  man.  Following  the  classification  of  Schaudinn  the  forms 
observed  in  schizogony  are  known  as  the  schizont  and  the  merozoite,  the  first 
term  being  applied  to  the  parasites  from  their  earliest  development  in  the  red 
blood-corpuscles  to  the  time  of  sporulation,  while  the  latter  term  is  applied  to 
the  liberated  spore;  these  forms  occur  only  in  the  blood  of  man  and  are  unable 
to  develop  outside  of  the  human  body.  The  forms  of  the  plasmodia  observed  in 
human  blood,  and  which  are  intended  to  undergo  development  in  the  b«dy  of 
the  mosquito,  are  known  as  gametes,  ard  are  sexually  differentiated,  the  female 
gamete  being  known  as  the  macrogamete  and  the  male  as  the  micro gametocyte. 
These,  in  turn,  are  unable  to  undergo  development  in  the  human  body,  it 
being  necessary  that  they  reach  the  stomach  of  the  mosquito  before  further 
development  can  occur.  Under  certain  conditions  simulating  those  that  are 
present  in  the  stomach  of  the  insect,  the  micro gametocytes,  while  still  present  in 
human  blood  which  has  been  removed  for  examination,  undergo  further  develop- 
ment and  liberate  active  filaments,  the  micro  gametes,  which  penetrate  the 
macrogametes  and  fertilize  them;  this  process  occurs  normally  within  the 
mosquito,  but  inasmuch  as  it  can  be  observed  in  specimens  of  blood,  I  shall 
describe  the  forms  concerned  in  this  chapter,  together  with  the  forms  concerned 
in  schizogony. 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  19 

All  varieties  of  the  malarial  plasmodia  appear  at  first  within  the  red  blood- 
corpuscles  as  hyaline  disks  or  ring-like  bodies  devoid  of  motion.  The  forms 
which  undergo  schizogony  gradually  acquire  amoeboid  motility  and  develop 
a  certain  amount  of  pigment,  at  the  same  time  enlarging  and  encroaching  more 
and  more  upon  the  cell  containing  them.  The  pigment  is  derived  from  the 
haemoglobin  of  the  red  cell  which  is  destroyed  by  the  growth  of  the  plasmodium 
within  it.  After  a  certain  period  of  growth  the  plasmodia  divide  into  numerous 
minute  spores  which  are  liberated  by  the  rupture  of  the  red  corpuscles  containing 
them,  and  which  invade  other  corpuscles  and  repeat  the  process  of  development 
briefly  described.  Among  the  spores,  however,  which  are  liberated  at  the  time 
of  sporulation,  there  are  some  that  do  not  undergo  schizogony,  but  after  penetrat- 
ing the  red  blood-corpuscles  develop  into  forms  intended  to  undergo  their 
life  cycle  within  the  mosquito.  These  forms  do  not  sporulate,  but  grow  at  the 
expense  of  the  red  cell  and  are  finally  found  free  in  the  blood  plasma  from  which 
they  escape  when  the  blood  is  removed  by  the  mosquito.  These  bodies  may  be 
differentiated  into  two  varieties,  as  has  been  mentioned,  and  are  incapable  of 
further  development  in  man,  although  Schaudinn  believed  that  the  female 
form,  or  macrogamete,  if  not  removed  from  the  blood  by  the  mosquito,  after 
a  certain  period  of  time  underwent  parthenogenesis,  giving  rise  to  numerous 
young  spores  which  entered  the  red  corpuscles  and  developed  as  in  schizogony. 
Schaudinn  thus  explained  the  occurrence  of  relapses  in  malaria,  but  his  observa- 
tions still  await  confirmation. 

In  describing  the  malarial  plasmodia  as  observed  in  the  blood  of  man,  I 
shall  describe  each  species  separately,  first  giving  the  morphology  of  the  forms 
concerned  in  schizogony,  the  schizont  and  the  merozoite,  and  then  the  forms 
concerned  in  sporogony,  which  are  demonstrable  in  human  blood,  namely, 
the  macro  gametes,  the  micro  gametocyte  and  the  microgamete. 

The  Morphology  and  Biology  of  Plasmodium  Vivax  (the  tertian  malarial 
parasite).    Schizogony  (human  or  asexual  cycle). 

Plasmodium  vivax  or  the  tertian  malarial  parasite  completes  its  develop- 
ment in  the  blood  in  48  hours  and  produces  the  well-known  type  of  malarial 
fever  associated  with  a  chill  and  fever  occurring  upon  every  second  day.  This 
type  of  malaria  is  the  most  common  type  in  temperate  regions  and  in  many 
subtropical  and  tropical  localities,  and  has  been  more  thoroughly  studied  than 
has  any  other  form  of  the  disease.  The  organism  causing  this  variety  of 
malaria  is  the  most  easily  recognized  of  the  malarial  plasmodia  and  is  the  one 
which  should  be  selected  for  study  by  those  who  desire  to  acquire  proficiency 
in  the  recognition  of  the  various  stages  in  the  development  of  the  human 
plasmodia  and  the  forms  to  be  observed  in  the  peripheral  blood. 

Historical  Summary. — The  tertian  plasmodium  was  first  described  as  a 
distinct  species  by  Golgi  in  1886.  He  called  attention  to  differences  in  the 
morphology  of  this  plasmodium  as  compared  to  the  quartan  plasmodium,  and 
noted  that  sporulation  occurred  every  48  hours  instead  of  every  72,  as  in  the 
latter  parasite.      He  also  called  attention  to  the  rapid  amoebid  motion  of  this 


20 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 


Plasmodium;  the  light  red  color  of  the  pigment  and  the  smallness  of  the  grains; 
the  great  enlargement  of  the  infected  red  cells  and  their  rapid  loss  of  haemoglobin; 
and  the  difference  in  size  of  the  two  organisms,  the  tertian  when  fully  grown 
being  much  larger  than  the  quartan.  He  described  the  greater  number  of 
segments  or  spores  in  the  tertian  plasmodium,  their  smaller  size,  and  irregular 
arrangement.  Golgi  stated  that  a  quotidian  fever  might  be  due  to  a  double 
infection  with  the  tertian  plasmodium,  each  group  sporulating  upon  successive 
days. 

The  observations  of  Golgi  were  soon  confirmed  by  those  of  Antolisei  and 
Bastianelli  and  Bignami,  and  have  since  been  confirmed  by  every  student  of 
this  type  of  malaria. 

Unstained  Preparations. — The  tertian  malarial  plasmodium,  or  Plasmo- 
dium vivax,  appears  first  within  the  red  blcod-corpuscle  in  schizogony  as  a  small, 
non-motile,  hyaline  disk  or  "ring,"  the  trophozoite,  measuring  about  2  microns 
in  diameter;  its  outline  is  very  indistinct  and  in  many  instances  the  organism 
at  this  stage  of  its  development  is  overlooked  by  reason  of  the  absence  of 
amoeboid  motion  and  because  of  its  delicate,  veil-like  appearance.     As  the 


Fig.  i. — Plasmodium  vivax.  (Tertian 
plasmodium.)  Double  infection  of 
red  corpuscle  with  "ring  forms." 
Photomicrograph,    X  1200. 


Fig.  2. — Plasmodium  vivax.  (Tertian  plas- 
modium.) Young  amoeboid  forms.  Photo- 
micrograph,  X  1200. 


parasite  grows  older,  becoming  the  schizont,  it  develops  very  marked  amoeboid 
activity,  constantly  changing  its  shape,  but  is  still  indistinct  in  outline,  requiring 
very  careful  examination  to  distinguish  it  in  the  infected  red  corpuscle. 

In  the  course  of  from  six  to  eight  hours  minute  granules  of  a  reddish- 
brown  pigment  develop  within  the  hyaline  cytoplasm  and  the  outline  of  the 
organism  becomes  more  clearly  distinguishable.  The  pigment  is  of  a  peculiar 
reddish-brown  color,  and  in  the  form  of  very  fine  granules  arranged  irregularly 
throughout  the  protoplasm,  and  is  in  very  active,  dancing  motion,  produced 
by   currents   within    the    protoplasm.     As   development   proceeds   amoeboid 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  2  1 

motion  becomes  less  pronounced,  and  when  the  organism  is  fully  grown  no 
amoeboid  motion  can  be  detected.  The  pigment,  at  first  small  in  amount, 
increases  gradually  as  the  organism  enlarges,  is  actively  motile  until  just  before 
sporulation,  and  is  always  in  the  form  of  fine  granules  pretty  evenly  distributed 
throughout  the  cytoplasm  until  just  prior  to  segmentation  when  it  collects  in 
larger  masses  or  in  a  single  irregular  mass  (see  Fig.  3). 

In  the  beginning  of  its  development  the  plasmodium  occupies  but  a  small 
portion  of  the  red  corpuscle,  but  as  it  continues  to  grow  it  encroaches  more  and 
more  upon  the  infected  corpuscle,  until  when  full-grown  it  entirely  fills  the  cell 
which  is  much  swollen  and  decolorized.  The  growth  of  the  plasmodium  is 
gradual,  covering  48  hours,  at  the  end  of  which  time  it  divides  into  a  number  of 
small  segments  or  spores. 

At  the  end  of  24  hours  the  plasmodium  fills  more  than  half  of  the  red 
corpuscle,  contains  much  actively  motile  pigment,  and  varies  greatly  in  shape, 
due  to  the  marked  amoeboid  motion  of  the  organism.  Very  often  at  this  stage 
of  development  multiple  infections  of  the  red  cell  may  be  suspected  by  reason  of 
the  appearance  of  two  or  more  spherical  pigmented  bodies  in  the  same  red 
corpuscle,  but  careful  examination  will  reveal  the  fact  that  the  pigmented 
spherical  bodies  are  but  portions  of  the  amoeboid  pseudopodia  of  a  single 
orga  lism,  the  remainder  of  the  organism  being  situated  deeper  within  the 
infected  cell,  and  thus  rendered  invisible  for  the  time  being.  The  infected  red 
cell  at  this  stage  is  considerably  larger  than  normal  and  lighter  green  in  color 
(see  Fig.  3). 

At  the  end  of  36  hours  the  plasmodium  has  attained  its  greatest  size  and 
almost  fills  the  infected  corpuscle.  The  amoeboid  motion  is  sluggish,  but  the 
pigment,  which  has  still  further  increased  in  amount,  is  very  actively  motile, 
and  is  distributed  in  the  form  of  fine  granules  throughout  the  protoplasm;  the 
outline  of  the  plasmodium  is  well  defined,  contrasting  well  with  the  light  green 
border  of  the  red  corpuscle  which  surrounds  it.  The  infected  red  cell  is  almost 
twice  as  large  as  are  the  uninfected  cells  and  much  lighter  in  color  (see  Fig.  4) . 

At  the  end  of  48  hours  segmentation  or  sporulation  occurs;  the  pigment 
becomes  collected  at  the  center  or  to  one  side  of  the  plasmodium  in  the  form  of  a 
compact  clump,  and  fine  radial  striations  are  observed  extending  from  the  center 
toward  the  periphery  of  the  plasmodium,  dividing  it  into  several  avoid  segments 
or  spores.  As  a  rule,  these  spores  are  arranged  in  two  rows,  one  row  surrounding 
the  center  of  the  plasmodium  and  another  surrounding  the  first  row;  but  very 
often  the  spores  are  arranged  irregularly;  they  are  always  devoid  of  pigment, 
and  vary  in  number  from  12  to  24,  the  average  being  about  sixteen.  They  are 
called  merozoites.  In  the  fresh  specimen  the  merozoite  when  free  in  the  blood 
plasma,  measures  from  1.5  to  2  microns  in  diameter,  is  oval  in  shape,  almost 
colorless,  and  presents  a  spherical,  refractive  center,  and  a  less  refractive  mass 
of  protoplasm  surrounding  it.  The  merozoites  are  capable  of  penetrating  the 
red  blood-corpuscles  and  thus  the  human  life  cycle  or  schizogony  of  the  plasmo- 
dium is  continued  (see  Fig.  5). 


22  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

Staining  Reactions  of  Plasmodium  Vivax. — In  preparations  of  blood 
containing  Pla sm odium  vivax  stained  by  the  Romanowsky  method  or  any  of  its 
modifications  the  exact  structure  of  the  parasite  can  be  easily  demonstrated. 
The  staining  methods  which  are  of  value  in  the  study  of  the  malarial  plasmodia 
will  be  fully  described  in  a  later  chapter  of  this  work;  by  their  use  the  plasmodia 
are  shown  to  consist  of  a  mass  of  protoplasm,  and  a  vesicular  nucleus,  rich  in 
chromatin.  This  is  true  of  all  species  of  the  plasmodia,  but  the  structure  can  be 
more  easily  studied  in  Plasmodium  vivax  because  it  exceeds  the  other  species  in 
size  and  because  all  stages  of  its  development  can  be  observed  in  the  peripheral 
blood. 

Historical  Summary. — The  first  observations  upon  the  structure  of  the 
malarial  plasmodia  in  stained  specimens  of  blood  were  made  by  Celli  and  Guar- 
nieri,  who  used  methylene  blue  as  the  staining  reagent.  They  described  a 
deeply  stained  ectoplasm  and  a  dimly  stained  endoplasm,  the  latter  forming 
the  center  of  the  parasite.  In  the  "ring-forms"  they  described  a  deeply  stained 
spot  situated  between  the  ectoplasm  and  the  endoplasm,  which  later  observers 
have  demonstrated  to  be  the  chromatin  of  the  nucleus. 

Grassi  and  Feletti,  as  the  result  of  their  study  of  stained  malarial  parasites, 
considered  that  the  dimly  stained  endoplasm  described  by  Celli  and  Guarnieri 
was  in  reality  a  large  vesicular  nucleus,  containing  nuclear  juice,  a  nuclear  net- 
work, and  chromatin,  and  having  a  delicate,  generally  invisible,  nuclear  mem- 
brane ;  they  also  described  contractile  vacuoles  in  the  protoplasm  of  the  plasmodia 
and  note  that  it  is  only  the  protoplasm  that  contains  the  pigment  granules. 

Romanowsky,  using  his  now  well-known  staining  method,  demonstrated 
that  the  plasmodia  consist  of  an  outer,  deeply  stained  portion,  the  protoplasm, 
and  an  inner  unstained  portion,  the  nucleus.  The  latter  is  spherical  or  oval  in 
shape  and  presents  at  some  portion  of  its  periphery  a  deeply  stained  mass,  the 
chromatin  of  the  nucleus,  the  remainder  of  the  nucleus  being  unstained  and 
consisting  of  nuclear  juice.  This  description  applies  only  to  the  young  plasmodia, 
as  in  the  older  organisms  he  found  that  the  vesicular  nucleus  disappeared  and 
that  the  chromatin  became  distributed  in  the  protoplasm  of  the  plasmodia. 

The  observations  of  Romanowsky  regarding  the  structure  of  the  malarial 
plasmodia  have  been  again  and  again  confirmed,  and  but  little  has  been  added 
to  our  knowledge  in  this  direction  by  subsequent  observers,  with  the  exception 
of  the  differentiation  of  those  forms  concerned  in  sporogony.  It  may  be  stated 
that  the  staining  reactions  are  similar  for  all  species  of  human  plasmodia,  and 
that  they  prove  that  these  organisms  consist  of  a  mass  of  protoplasm,  containing 
at  some  period  of  development  more  or  less  pigment  and  a  vesicular  nucleus 
rich  in  chromatin. 

With  Wright's  modification  of  the  Romanowsky  stain,  which  I  habitually 
use,  and  which  I  have  found  most  satisfactory  in  staining  these  organisms,  the 
chromatin  is  the  only  portion  of  the  nucleus  which  takes  the  stain,  the  young 
schizont  consisting  of  a  deeply  stained  mass  of  chromatin,  surrounded  by  an  un- 
stained space,  which  in  turn  is  surrounded  by  the  deeply  stained  protoplasm. 
As  development  advances  the  chromatin  of  the  nucleus  divides,  becomes  dis- 
tributed in  the  protoplasm  where  it  stains  in  a  characteristic  manner,  increases 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  2  7, 

in  amount,  and  finally  becomes  collected  into  small  masses  forming  the  chro- 
matic portion  of  the  nucleus  of  the  merozoites. 

In  schizogony,  if  Wright's  method  of  staining  be  employed,  Plasmodium 
vivax  presents  the  following  staining  reactions  during  its  various  stages  of 
development: 

The  youngest  sclnzont,  which  develops  from  the  trophozoite  shortly  after  the 
latter  infects  the  red  blood-corpuscle,  presents  the  so-called  "ring-form,"  con- 
sisting of  a  spherical  mass  of  chromatin  stained  a  brilliant  red  or  violet,  sur- 
rounded by  an  unstained  spherical  or  oval  area;  this  area  often  presents  a  milky 
white  color  and  is  in  contact  at  one  portion  of  its  periphery  with  a  spherical, 
unstained  area,  considerably  larger  than  the  milky  area,  which  appears  to  be 
stained  in  the  same  manner  as  the  red  blood  cell.  The  milky  zone,  as  it  is 
called,  represents  the  unstained  portion  of  the  vesicular  nucleus,  while  the  larger 
area,  stained  apparently  in  the  same  way  as  the  red  cell,  represents  a  vacuole 
which  has  developed  by  the  side  of  the  nucleus.  Immediately  surrounding  the 
vacuole  and  the  vesicular  nucleus  is  a  ring-like  mass  of  protoplasm  stained  a 
deep  blue;  this  ring  of  protoplasm  is  very  thin  at  one  portion  of  its  periphery 
where  it  almost  comes  in  contact  with  the  chromatin  which  is  situated  eccen- 
trically in  the  nucleus.  The  appearance  of  the  plasmodium  at  this  stage  is  that 
of  a  blue  ring  of  protoplasm  surrounding  an  area  of  the  color  of  the  red  cell,  at 
one  portion  of  which  is  a  spherical  milky  area  containing  a  bright  red  mass  of 
chromatin  (see  Fig.  i). 

In  those  schizonts  in  which  limited  amoeboid  motion  was  present  at  the 
time  of  fixation  of  the  specimens,  many  forms  of  the  "ring"  may  be  observed, 
due  to  minute  pseudopodia  arising  from  the  protoplasm  of  the  plasmodium. 
In  very  many  instances  it  will  be  observed  that  the  protoplasm  is  thicker  at 
i  certain  portions  or  very  delicate  filaments  of  blue-stained  cytoplasm  may'  be 
seen  connecting  various  portions  of  the  periphery  of  the  "ring";  in  such  in- 
stances the  chromatin  mass  may  be  situated  at  any  portion  of  the  protoplasmic 
filaments,  very  often  at  their  extremity,  or  at  the  point  of  attachment  to  the 
body  of  the  plasmodium.  The  vacuole  in  such  plasmodia  cannot  be  distin- 
guished (see  Fig.  2). 

As  the  schizont  becomes  larger  and  pigment  begins  to  appear  we  observe 
that  the  latter  is  situated  in  the  cytoplasm  of  the  parasite,  which,  by  reason  of 
their  active  amoeboid  motion,  present  in  stained  specimens  many  bizarre 
forms.  The  unstained  vesicular  nucleus  is  still  present  and  contains  the  chroma- 
tin, which  has  divided  into  delicate  filaments  and  dots,  staining  pink,  but  less 
intensely  than  when  it  was  collected  in  a  compact  mass.  The  nuclear  vacuole 
may  be  present  after  pigment  formation,  but  at  a  later  period  of  development 
both  it  and  the  vesicular  portion  of  the  nucleus  disappear,  and  the  chromatin 
becomes  distributed  in  the  cytoplasm  in  the  form  of  minute  filaments  and 
granules,  which  may  stain  intensely,  but  generally  very  dimly.  At  a  certain 
period  of  development  the  chromatin  divides  into  very  fine  filaments  and  only 
prolonged  staining  will  demonstrate  its  presence.     In  those  plasmodia  in  which 


24  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

the  vacuole  is  present,  it  appears  as  a  round  or  oval,  unstained  area,  surrounded 
by  the  blue-stained  cytoplasm. 

As  the  time  for  sporulation  approaches  this  plasmodium  presents  very 
marked  changes  in  its  structure.  The  cytoplasm  increases  in  amount,  stains  a 
deep  blue,  and  is  heavily  pigmented.  The  chromatin  also  increases  in  amount, 
is  collected  in  irregular  clumps,  and  stains  an  intense  red  or  violet;  the  filament- 
ous structure  of  the  chromatin  has  disappeared  and  it  now  consists  of  large 
grains  and  compactly  formed  masses  arranged  irregularly  throughout  the 
protoplasm.     The  vesicular  portion  of  the  nucleus  has  disappeared. 

In  the  presegmenting  plasmodia,  the  protoplasm,  containing  the  pigment 
granules,  stains  a  well-defined  blue,  the  pigment  being  arranged  in  irregular 
masses  staining  a  peculiar  greenish-brown.  The  chromatin,  staining  an  in- 
tense red,  is  collected  into  roughly  spherical  masses,  arranged  more  or  less 
regularly  in  the  cytoplasm,  which  as  yet  shows  little  evidence  of  division. 

In  the  segmenting  or  sporulating  plasmodia  the  chromatin  is  collected  in 
compact,  deep  red  spherical  masses,  each  surrounded  by  an  unstained  area,  in 
turn  surrounded  by  a  small  mass  of  cytoplasm;  the  pigment  is  collected  into  a 
single  clump  or  in  irregular  masses  situated  in  a  small  portion  of  residual  proto- 
plasm. When  the  infected  red  cell  disintegrates,  the  segments  or  merozoites 
are  liberated,  the  pigment  and  residual  protoplasm  are  engulfed  by  leucocytes, 
and  the  merozoites  again  infect  red  blood-corpuscles. 

Each  merozoite,  when  stained  by  Wright's  method,  is  seen  to  consist  of  a 
mass  of  protoplasm  stained  a  deep  blue,  enclosing  an  unstained  oval  area  which 
contains  a  spherical  dot  of  chromatin  stained  a  deep  red  or  violet.  The  chroma- 
tin is  placed  eccentrically  and  the  protoplasm  is  much  thicker  at  that  portion  of 
the  parasite  furthest  removed  from  the  nucleus.  The  merozoites  measure  from 
1.5 'to  2  microns  in  diameter. 

The  description  of  Plasmodium  vivax  which  has  been  given  refers  only  to 
the  forms  concerned  in  the  human  cycle  of  development  or  schizogony,  the 
development  of  the  plasmodium  having  been  traced  from  its  entrance  into  the 
red  blood-corpuscle  to  sporulation.  Schizogony  is  initiated  in  nature  by  the 
entry  into  the  red  blood-corpuscles  of  sporozoites  introduced  into  the  blood  of 
man  by  the  bite  of  an  infected  mosquito.  After  entry  into  the  red  cells  the 
sporozoites  become  trophozoites  and  are  of  two  varieties,  those  which  develop  into 
schizonts  and  continue  the  infection  in  man,  and  those  which  develop  into 
gametes,  intended  to  continue  the  infection  in  the  mosquito.  The  trophozoites 
which  are  destined  to  become  schizonts  are  characterized  by  the  "ring-form," 
and  such  forms  always  greatly  out-number  the  trophozoites  which  develop  into 
gametes. 

Changes  in  the  Infected  Blood-corpuscles. — The  changes  which  occur 
in  the  red  blood-corpuscles  infected  with  Plasmodium  vivax  are  of  great  impor- 
tance from  a  diagnostic  standpoint,  as  these  changes  alone  will  suffice  to 
differentiate  this  plasmodium  from  either  the  quartan  or  aestivo-autumnal 
plasmodia. 


THE    ETIOLOGY    OF    THE    MALARIAL    FKVKKS. 


25 


The  red  corpuscle  infected  with  Plasmodium  vivax  is  always  larger  than 
normal,  even  when  the  parasite  is  in  the  earliest  stages  of  development.  Not 
only  is  the  red  cell  enlarged,  but  it  is  paler  in  color  than  normal, and  in  examining 
the  blood  for  the  tertian  plasmodium  it  is  often  most  easily  discovered  by 
selecting  the  red  cells  which  appear  larger  and  paler  than  normal  and  carefully 


Fig.  3. — Plasmodium  vivax.  (Tertian 
Plasmodium.)  Half-grown  parasite. 
Photomicrograph,   X  1200. 


Fig.  4. — Plasmodium  vivax.  (Tertian 
Plasmodium.)  Presegmenting  para- 
site.    Photomicrograph,   X  1200. 


examining  them.  While  the  enlargement  is  not  marked  before  the  plasmodia 
become  pigmented,  the  red  cell  enlarges  rapidly  after  pigmentation  occurs,  and 
when  the  plasmodium  is  fully  developed  is  generally  twice  as  large  as  an  unin- 
fected corpuscle,  and  almost  devoid  of  color.  In  the  stained  specimens  the 
enlargement  is  very  noticeable  and  the  corpuscle  is  often  much  distorted  in 


Fig.   5. — Plasmodium   vivax.     (Tertian  plasmodium.)     Sporulatim 
parasite.     Photomicrograph,    X  1200. 


shape.  A  very  important  degenerative  change  occurring  in  red  cells  infected 
with  the  tertian  plasmodium  leads  to  the  occurrence  of  small  refractive  granules 
situated  within  the  protoplasm  and  which  stain  a  reddish  color  when  the 
Romanowsky  stain  or  any  of  its  modifications  are  used.  With  Wright's  stain 
this  red  stippling  of  the  infected  red  corpuscle  is  well  marked,  and  such  cells  are 


26  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

known  as  "stippled  cells,"  and  the  granules  as  Schuffner's  granules  or  dots.  In 
those  cells  containing  the  youngest  "ring-forms"  Schuffner's  dots  may  not  be 
present,  but  after  pigment  appears  almost  every  infected  corpuscle  will  show 
this  form  of  degeneration  in  stained  specimens. 

The  occurrence  of  these  granules  is  of  great  importance  in  making  a 
differential  diagnosis  between  the  tertian  plasmodium  in  its  early  stages  of 
development  and  similar  stages  of  development  of  the  quartan  plasmodium. 
While  I  have  very  rarely  seen  Schuffner's  dots  in  cells  infected  with  undoubted 
quartan  plasmodia,  contrary  to  the  statements  of  certain  authorities  who 
believe  that  this  form  of  degeneration  occurs  only  in  tertian  infection,  the  occur- 
rence is  of  such  great  rarity  as  to  be  of  no  practical  importance,  and  malarial 
infections  in  which  Schuffner's  dots  are  found  in  the  infected  red  cells  may 
practically  always  be  diagnosed  as  tertian  infections,  provided,  of  course,  that  a 
double  infection  with  some  other  species  of  plasmodium  be  not  present. 

The  occurrence  of  these  granules  in  cells  containing  the  "ring-forms"  is 
conclusive  proof  that  these  rings  are  of  the  benign  tertian  variety,  for  Schuffner's 
granules  never  occur  in  cells  infected  with  "ring-forms"  of  the  quartan  or 
aestivo-autumnal  plasmodia. 

The  characteristic  changes  occurring  in  the  red  blood-corpuscle  infected 
with  Plasmodium  vivax  are  the  following:  enlargement  at  every  stage  of  develop- 
ment of  the  plasmodium;  decolorization  progressive  with  the  growth  of  the 
plasmodium;  changes  in  shape,  and  the  occurrence  of  Schuffner's  granules  or  dots 
in  the  protoplasm  of  the  cell.  As  it  is  probable  that  this  form  of  degeneration  of 
the  protoplasm  of  the  infected  red  cell  is  due  to  certain  poisonous  products 
elaborated  by  the  plasmodium  during  its  development,  and  as  these  granules 
occur  almost  exclusively  in  infections  with  Plasmodium  vivax,  it  is  evident  that 
this  organism  elaborates  certain  poisonous  materials  differing  from  those  elabo- 
rated by  the  other  species  of  plasmodia. 

The  Morphology  and  Biology  of  Plasmodium  Malariae.  (the 
quartan  malarial  parasite).  Schizogony  (human  or  asexual  cycle). 

Plasmodium  malariae,  or  the  quartan  malarial  parasite,  completes  its  develop- 
ment in  the  blood  of  man  in  72  hours,  producing  that  type  of  malarial  fever 
characterized  by  a  chill  and  a  rise  in  temperature  at  the  end  of  every  third 
day.  This  is  the  most  uncommon  form  of  malarial  infection,  and  in  some 
localities  is  so  rare  as  to  be  observed  but  a  few  times  in  many  thousand  cases  of 
malarial  disease.  All  stages  of  development  common  to  schizogony  occur  in  the 
peripheral  blood,  and  the  organism  is  easily  differentiated  from  the  other  species 
of  malarial  plasmodia. 

Historical  Summary. — The  description  of  this  species  of  human  plasmodium 
marked  the  first  attempt  to  divide  the  plasmodia  into  distinct  species,  and  to 
Golgi,  who,  in  1886,  described  very  fully  this  organism,  we  owe  the  recognition 
of  it  as  a  definite  species.  He  studied  22  cases  of  quartan  fever  and  followed 
the  complete  cycle  of  the  development  of  this  plasmodium  in  the  blood  of  the 
cases  studied.      He  called  attention  to  the  rela+ion  of  sporulation  to  the  clinical 


EXPLANATION   OF  PLATE  I. 

Tertian  Plasmodium.      (Plasmodium  vivax.)      Unstained  specimens, 
i.    Normal  red  blood-corpuscle. 

2.  Hyaline  "ring  form." 

3,  4,  5.   Young  pigmented  forms. 

6.  Pigmented  form,  nearly  half-grown. 

7.  Three-quarters  grown  pigmented  form. 

8.  Full  grown  pigmented  plasmodium. 

9.  10.   Sporulating  plasmodium. 

11.  Macrogamete. 

12.  Microgametocyte.      (Flagellated  body.) 

(Note  the  gradual  enlargement  of  the  infected  red  blood-corpuscle,  and  the 
diminution  in  the  haemoglobin.) 

Quartan  Plasmodium.      (Plasmodium  malaria.)      Unstained  specimens. 

1.  Normal  red  blood-corpuscle. 

2.  Hyaline  plasmodium. 

3.  Young  pigmented  plasmodium. 

4  to  11.    Various  stages  in  the  growth  of  the  pigmented  plasmodia. 

11.  Full-grown  pigmented  plasmodium. 

12,  13.   Sporulating  plasmodia. 
14.   Macrogamete. 

1  5.    Vacuolated  macrogamete. 
16.   Microgametocyte.      (Flagellated  body.) 
Quotidian    Aestivo-autumnal    Plasmodium.      (Plasmodium,   falciparum,   quotidi- 
anum.)      Unstained  specimens. 
1.    Normal  red  blood-corpuscle. 

2  to  8.   Various  hyaline  "ring  forms"  of  the  plasmodium. 
8,  9,  10.   Pigmented  forms  of  the  plasmodium. 

11.  Intracorpuscular  crescent,      (gamete.) 
'  12  and  13.   Sporulating  plasmodia. 

14.  Macrogamete.     '(Female  crescent.) 

15.  Microgametocyte.      (Male  crescent.) 

16.  Flagellated  form  of  microgametocyte. 

Tertian  Aestivo-autumnal  Plasmodium.      (Plasmodium  falciparum.) 

1.  Normal  red  blood-corpuscle. 

2.  Hyaline  "ring  form." 

3,4,  5.   Pigmented  "ring  forms"  of  the  plasmodium. 
6,  8,  9,  10,  11.      Pigmented  forms  of  the  plasmodium. 

12.  Sporulating  form  of  the  plasmodium. 

13.  Macrogamete. 

14.  Microgametocyte. 

15.  Ovoid  macrogamete. 

16.  Flagellated  form  of  microgametocyte. 


1 


Plate  I 


% 


4 


m  »»&r* 


W4Hr 


Igf 


mm* 

2 
10 


Tertian  Plasmodium. 


'* 


11  12 


13 


Quartan  Plasmodium. 


S 


7 


--■■>.  ■...--.:. 


1 
9 


10 


11 


15  16 


Quotidian  Aestivo-autumnal  Plasmodium. 


10  11  12  13  14  15 

Tertian  Aestivo-autumnal  Plasmodium.  c.  f.  craig.  del. 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  27 

symptoms,  the  chill  and  fever  occurring  at  the  end  of  every  72  hours,  at  which 
time  segmentation  of  the  plasmodia  always  occurred.  He  described  very 
carefully  the  morphology  of  the  organism  during  its  various  stages  of  develop- 
ment, noted  that  the  more  severe  the  clinical  symptoms  the  greater  the  number 
of  plasmodia  in  the  blood,  and  that  infection  with  three  groups  of  this  Plasmo- 
dium resulted  in  a  quotidian  fever 

Golgi's  observations  regarding  Plasmodium  malariae  were  confirmed  by 
Osier  in  same  year  and  by  Antolisei  in  1890,  and  this  species  has  been  accepted 
by  almost  every  observer  who  has  had  the  opportunity  of  studying  quartan 
malarial  infections. 


Unstained  Preparations. — Like  the  tertian  plasmodium,  the  organism 
causing  quartan  malaria,  or  Plasmodium  malaria,  appears  at  first  within  the 
red  blood-corpuscle  as  a  small  amoeboid  body  called  the  trophozoite.  It  is 
sluggishly  amoeboid  as  compared  to  the  benign  tertian  plasmodium,  and  is 
hyaline  in  appearance.  Those  trophozoites  which  are  to  undergo  schizogony 
soon  develop  into  schizonts,  while  those  intended  to  undergo  development 
in  the  mosquito  develop  into  gametes.  The  quartan  schizont  is  a  small, 
sluggishly  amoeboid,  hyaline  body,  measuring  about  1.8  to  2.5  microns  in 
diameter,  at  its  earliest  stage  of  development.  Although  at  this  period  of 
development  these  organisms  are  believed  to  be  indistinguishable  from  similar 
forms  of  the  benign  tertian  plasmodium,  there  is,  in  reality,  but  little  difficulty 
in  distinguishing  them,  the  quartan  schizont  being  much  more  sharply  cut 
and  refractive  and  the  infected  red  cell  not  enlarged  and  slightly  more  greenish 
in  color. 

"Within  a  few  hours  the  quartan  plasmodium  begins  to  develop  pigment 
in  the  form  of  a  few  rather  coarse  granules  of  a  dark  brown  color,  situated  at 
the  periphery  of  the  organism  and  possessing  but  very  little  motility,  thus 
differing  from  the  pigment  in  Plasmodium  vivax,  which  is  in  the  form  of  very 
minute  reddish-brown  granules,  very  actively  motile.  At  this  early  pigmented 
stage  the  plasmodium  is  very  sluggish  in  its  amoeboid  movements,  and  is 
generally  of  a  spherical  or  triangular  shape,  filling  about  one-quarter  of  the  red 
corpuscle,  which  is  not  in  the  least  enlarged. 

The  plasmodium  slowly  increases  in  size,  and  in  doing  so  loses  its  amoeboid 
motility;  the  pigment  increases  in  quantity  and  becomes  collected  at  he  ex- 
treme periphery  of  the  organism  in  the  form  of  large,  very  dark  brown  grains 
which  are  absolutely  immotile.  The  protoplasm  of  the  plasmodium  is  very 
distinct  and  appears  to  be  of  greater  consistence  than  the  protoplasm  of  Plas- 
modium vr,  ax.  The  infected  red  corpuscle  is  normal  in  size  and  slightly  darker 
in  color. 

In  24  hours  the  distinguishing  features  of  the  quartan  plasmodium  are 
fully  developed.  The  organism  is  sharply  outlined,  is  very  refractive,  and  its 
protoplasm  often  presents  a  peculiar,  very  finely  granular  appearance;  the 
pigment  is  dark  brown  in  color,  in  the  form  of  coarse  granules,  and  is  generally 
collected  around  the  edge  of  the  plasmodium,  sometimes  forming  an  almost 


28  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

complete  wreath  around  it;  the  pigment  is  motionless.  The  shape  of  the 
Plasmodium  at  this  stage  of  development  is  usually  triangular,  ovoid,  or  round, 
and  it  occupies  about  one-half  of  the  infected  red  cell.  Amoeboid  motion  is 
generally  absent.  The  invaded  corpuscle  is  smaller,  if  anything,  than  the 
healthy  ones  and  is  of  a  darker  green  color  (see  Fig.  6). 

At  the  end  of  36  hours  all  of  the  phenomena  noted  are  more  pronounced, 
the  organism  filling  about  two-thirds  of  the  corpuscle,  which  appears  to  be 
retracting  about  it;  the  pigment  is  increased  in  amount,  is  motionless,  and 
collected  in  rough  masses  at  the  border  of  the  plasmodium.  Amoeboid  motion 
is  entirely  absent.  The  growth  of  Plasmodium  malar  iae  from  this  time  on  is 
very  slow,  and  it  is  not  until  about  eight  hours  before  sporulation  that  preseg- 
menting  forms  are  to  be  seen  in  the  peripheral  blood.  Such  plasmodia  are 
spherical  in  shape,  bordered  by  a  thin  greenish  layer  representing  the  remains 
of  the  infected  red  corpuscle.  Numerous  clumps  of  dark  brown,  sometimes 
almost  black,  pigment  are  present  in  the  protoplasm,  not  now  confined  to  the 
periphery  of  the  plasmodium,  but  scattered  through  the  protoplasm  in  an 
irregular  manner.  The  pigment  is  not  motile  nor  is  amoeboid  motion  present 
in  the  plasmodium.  The  infected  red  cell  is  slightly  smaller  than  the  normal 
corpuscles  and  distinctly  darker  in  color  (see  Fig.  7). 

In  many  instances  segmentation  or  sporulation  occurs  before  the  red 
corpuscle  is  completely  filled  by  the  plasmodium,  the  pigment  collecting 
toward  the  center  of  the  plasmodium  and  six  or  more  segments  or  spores 
appearing  within  the  corpuscle.  More  commonly,  however,  at  the  end  of  72 
hours,  the  plasmodium  entirely  fills  the  invaded  cell  and  sporulation  occurs 
in  the  following  manner:  the  pigment  becomes  collected  at  the  exact  center 
of  the  plasmodium  in  a  solid,  almost  black,  spherical  mass,  or  in  a  star-like 
arrangement  distributed  from  the  center,  and  about  the  same  time  all  trace 
of  the  infected  red  corpuscle  disappears,  the  plasmodium  being  apparently 
extracellular;  in  a  short  time  radial  striations  are  observed  shooting  out  from 
the  pigmented  center,  and  these,  joining  at  their  extremities,  form  from  six 
to  fourteen  oval  segments  or  spores,  the  merozoites.  As  a  rule,  the  number 
of  spores  does  not  exceed  ten.  The  spores  are  generally  arranged  in  a  per- 
fectly symmetrical  manner  around  the  central  pigment  in  a  single  row,  giving 
the  so-called  daisy  or  "Marguerite"  appearance  to  the  plasmodium  at  this 
stage.  The  number  and  the  beautifully  regular  arrangement  of  the  merozoites 
would  alone  serve  to  distinguish  this  stage  of  the  quartan  from  the  corres- 
ponding stage  of  the  tertian  plasmodium,  but  the  quartan  merozoites  are  also 
more  oval  in  shape,  more  refractile  and  somewhat  larger,  measuring  about  2.5 
microns  in  diameter  (see  Fig.  8). 

When  segmentation  is  complete  each  merozoite  becomes  free  in  the  blood 
plasma  and,  in  the  human  cycle,  again  invades  the  red  corpuscles,  some 
becoming  schizonts,  while  others  become  gametes. 

At  the  time  of  sporulation  the  pigment  and  the  residual  protoplasm 
containing  it  is  liberated  and  most  of  it  is  engulfed  by  phagocytic  leucocytes, 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 


2Q 


some  of  the  pigment,  however,  remaining  free  in  the  Mood  for  a  considerable 
time.  There  is  a  slight  difference  in  size  between  individual  sporulating  bodies, 
even  in  the  same  individual,  and  rarely  sporulation  may  be  observed  in  plasmodia 
that  do  not  occupy  more  than  two-thirds  of  the  red  corpuscle,  but  as  a  general 


Fig.  6. — Plasmodium  malarias.     (Quartan  plasmodium.)     Presegmenting 
parasite.     Photomicrograph,   X  1200. 

rule  there  is  not  as  much  variation  in  the  size  of  the  sporulating  forms  of 
Plasmodium  malariae  as  there  is  in  the  same  forms  of  Plasmodium  vivax. 
The  star-like  arrangement  of  the  pigment  between  the  segments,  which  Thayer 
considers  so  characteristic,  is  generally  observed,  but  I  have  observed  exactly 


Fig.  7. — Plasmodium  malarias.  (Quartan 
Plasmodium.)  Sporulating  parasite. 
Photomicrograph,    X  1200. 


Fig.  8. — Plasmodium  malariae.  (Quartan 
Plasmodium.)  Sporulating  parasite 
Photomicrograph,    X  1800. 


the  same  arrangement  of  pigment  in  tertian  segmenting  forms;  it  is  probably 
of  accidental  occurrence,  doubtless  more  common  in  the  quartan  plasmodium, 
but  not  at  all  peculiar  to  the  species. 

Staining    Reactions    of    Plasmodium   Malariae. — The    structure    of 
Plasmodium  malariae,  the  quartan  malarial  parasite,  as  shown  by  Wright's 


30  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

method  of  staining,  is  similar  to  that  of  Plasmodium  vivax,  the  benign  tertian 
parasite,  in  that  it  consists  of  a  small  amount  of  protoplasm  surrounding  a 
vesicular  nucleus  rich  in  chromatin,  but  certain  differences  exist  in  the  staining 
qualities  of  the  protoplasm  and  nucleus  of  the  plasmodium,  and  of  the  infected 
red  corpuscle  which  are  of  service  in  differentiating  this  species  from  the  plasmo- 
dium of  tertian  malaria  or  the  plasmodia  of  the  aestivo-autumnal  infections. 

The  youngest  schizont  when  stained  is  larger  than  the  schizont  of  the  tertian 
Plasmodium,  but  exhibits  the  same  ring-like  appearance,  consisting  of  a  blue 
ring  of  protoplasm  surrounding  a  milky  spherical  zone  containing  the  red 
chromatin  and  a  vacuole,  developed  at  one  side  of  the  nucleus.  The  proto- 
plasm of  the  plasmodium  of  quartan  fever  stains  a  deeper  blue  than  does  that  of 
the  tertian  organism,  and  the  chromatin,  which  stains  a  very  dark  red,  is  situated 
nearer  the  center  of  the  milky  or  vesicular  portion  of  the  nucleus.  The  vacuole, 
which  causes  the  "ring"  at  this  stage  of  development  is  only  observed  in  those 
plasmodia  that  are  destined  to  become  schizonts. 

The  staining  reactions  during  later  stages  of  development  are  like  those  of 
Plasmodium  vivax,  already  described,  the  vacuole  disappearing  and  with  it  the 
"ring-form,"  the  organism  spreading  out  into  the  red  cell,  finally  filling  it. 
The  protoplasm  throughout  development  stains  more  intensely  blue  than  that  of 
the  tertian  plasmodium,  and  the  chromatin  a  more  intense  red.  The  latter, 
when  distributed  throughout  the  protoplasm,  is  in  the  form  of  larger,  thicker 
filaments,  in  more  definite  clumps  than  is  the  chromatin  of  Plasmodium  vivax, 
and  in  the  presegmenting  and  segmenting  forms  the  chromatin  is  in  more  com- 
pact clumps  or  masses  and  stains  a  darker  red  in  color.  Around  each  mass  of 
chromatin  in  these  fully  developed  forms  there  is  an  unstained  milky  area, 
representing  the  vesicular  portion  of  the  nucleus  of  the  developing  merozoites. 
Because  of  the  deeper  staining  and  circular  form  of  the  quartan  plasmodia, 
their  outline  is  much  more  distinct  in  stained  preparations  than  in  the  case  of 
the  tertian  plasmodium,  and  in  the  nearly  full-grown  forms  the  red  cell  is  very 
plainly  visible  as  a  narrow  rim  of  pink-stained  protoplasm  surrounding  the 
perfectly  circular  plasmodium. 

If  stained  preparations  be  made  during  the  second  day  of  development  the 
very  characteristic  "band  forms"  of  the  Plasmodium  malariae  can  be  observed, 
consisting  of  a  band  of  deep  blue  protoplasm  stretching  across  the  infected  red 
corpuscles,  enclosing  a  mass  of  chromatin  stained  an  intense  red  color.  I  have 
never  observed  such  "band  forms"  in  any  other  variety  of  malarial  infection, 
and  a  diagnosis  of  quartan  malarial  fever  is  justified  when  such  forms  are 
present. 

The  merozoites  or  spores  consist  of  a  deep  blue  mass  of  protoplasm  and  of 
a  compact  mass  of  dark  red  chromatin  situated  eccentrically  in  relation  to  the 
protoplasm.  The  chromatin  in  most  instances  is  surrounded  by  a  very  small 
unstained  area,  the  vesicular  portion  of  the  nucleus. 

The  pigment  in  the  quartan  plasmodium  is  but  little  affected  by  the  stain, 
appearing  a  dark  brown  in  color,  although  in  those  instances  in  which  it  is 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  3 1 

collected  in  loosely  arranged  masses  the  stain  gives  it  a  very  well-defined  green- 
ish-brown tinge. 

Changes  in  the  Infected  Blood-corpuscle. — The  changes  observed  in 
the  infected  red  blood- corpuscle  in  quartan  malarial  fever  are  less  marked  than 
those  occurring  in  tertian  infections,  but  are  fully  as  characteristic.  A  study  of 
such  infections  as  regards  the  blood  will  convince  the  most  skeptical  that 
Plasmodium  malariae  produces  an  entirely  different  effect  upon  the  cells  in- 
vaded by  it  than  does  Plasmodium  vivax.  It  will  be  remembered  that  the  red 
corpuscles  invaded  by  the  latter  organism  increased  greatly  in  size,  due  to  their 
distention  by  the  growing  parasite,  and  became  much  paler  in  color.  In  in- 
fections with  Plasmodium  malariae  the  red  cell  instead  of  enlarging  remains 
normal  in  size,  or  more  often  becomes  smaller  than  the  uninfected  cells,  and 
instead  of  becoming  paler  in  color  is  darker  green  than  the  healthy  red  cells. 
It  would  appear  that  in  quartan  malaria  the  plasmodium  causes  a  shrinkage  of 
the  red  corpuscle  about  it  during  its  development  instead  of  expanding  the  red 
cell  as  does  the  tertian  plasmodium. 

I  have  already  spoken  of  the  occurrence  of  Schuffner's  granules  or  dots 
which  are  observed  within  the  cytoplasm  of  the  invaded  red  corpuscles  in  tertian 
infections;  such  a  form  of  degeneration  is  probably  never  present  in  quartan 
infections,  although  in  a  very  few  such  infections  I  have  observed  a  stippling 
indistinguishable  from  that  produced  by  Schuffner's  dots  in  invaded  red  blood- 
corpuscles.  However,  such  an  appearance  occurs  so  rarely  that  it  is  of  no 
practical  importance  and  does  not  alter  the  fact  that  the  presence  of  Schuffner's , 
dots  in  a  red  corpuscle  infected  with  a  malarial  plasmodium  indicates  that  the 
organism  present  is  Plasmodium  vivax. 

The  lack  of  enlargement  of  the  infected  red  blood-corpuscle,  its  darker 
green  color,  and  the  absence  of  Schuffner's  dots  serve  to  differentiate  Plasmo- 
dium malariae  and  Plasmodium  vivax,  the  red  cells  infected  with  the  quartan 
plasmodium  exhibiting  all  of  the  characteristics  mentioned,  but  are  of  no  value 
in  differentiating  Plasmodium  malariae  from  the  plasmodia  of  the  aestivo- 
autumnal  infections  which  produce  very  similar  changes  within  the  red  cor- 
puscles. In  the  latter  infections,  however,  other  changes  occur  within  the  red 
cells  which  serve  to  make  the  distinction  possible. 

As  in  the  tertian  infections,  certain  of  the  merozoites  produced  by  the 
sporulation  of  the  quartan  plasmodium,  and  certain  of  the  sporozoites  intro- 
duced by  the  bite  of  the  infected  mosquito  do  not  develop  into  schizonts  and 
undergo  schizogony,  but  develop  into  gametes,  which  undergo  sporogony  within 
the  mosquito.  These  forms  will  be  described  after  we  have  considered  the 
schizogony  of  the  aestivo-autumnal  plasmodia. 

The  Plasmodia  of  Aestivo-autumnal  Malarial  Fevers. — As  I  have 
already  stated  I  believe  that  the  plasmodia  causing  the  aestivo-autumnal 
malarial  fevers  are  divided  into  two  distinct  species,  which  differ  from  one 
another  in  morphology,  in  their  period  of  development,  and  in  the  pathogenic 
conditions  they  bring  about  in  the  infected  individual.     Many  observers  hold 


32  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

that  there  is  but  one  aestivo-autumnal  plasmodium,  which  varies  in  its  morphol- 
ogy and  the  period  of  time  required  for  its  development,  but  from  over  ten 
years'  study  of  malarial  infections  of  this  type  I  am  forced  to  conclude  that  these 
authorities  are  mistaken  and  that  two  forms  of  aestivo-autumnal  fever  occur, 
each  form  due  to  a  specific  plasmodium.  That  quotidian  and  tertian  forms  of 
aestivo-autumnal  malaria  exist  has  been  abundantly  proven  by  Marchiafava 
and  Bignami,  Bastianelli,  Caccini,  Mannaberg,  James,  Manson,  Jackson,  and 
myself,  as  well  as  others,  and  the  plasmodia  concerned  in  their  etiology  have 
been  carefully  studied  and  described. 

Historical  Summary. — Golgi,  in  1885,  was  the  first  to  call  attention  to  the 
probably  distinct  type  of  the  crescentic  and  ovoid  parasite,  and  suggested  the 
possibility  of  its  being  a  distinct  species  of  the  malarial  plasmod  .  ;  but  to  Council- 
man we  owe  the  first  statement  of  the  diagnostic  value  of  these  forms.  In  1887 
he  says :  ' '  The  character  of  these  bodies  (the  malarial  parasite)  varies  in  different, 
forms  of  the  disease.  Although  they  seem  in  some  cases  to  run  into  one  another, 
still,  in  general,  we  can  say  that  where  the  plasmodia  inside  the  red  corpuscles 
are  seen  (large  pigmented  forms)  the  patient  has  intermittent  fever,  and  where 
the  crescentic  and  elongated  forms  are  found  he  has  either  some  form  of  remittent 
fever  or  malarial  cachexia.  We  are  not  only  able  to  diagnose  the  disease  as  such, 
but  in  most  cases  the  particular  form." 

Golgi,  in  1889,  was  the  first  to  observe  that  the  small,  hyaline,  intracellular 
rings  and  the  crescent  and  the  ovoid  pigmented  bodies  were  associated  with 
malarial  fevers  of  remittent  character  with  long  intervals  between  the  parox- 
ysms. He  believed  that  the  ring  forms  were  the  first  stages  of  the  crescent  and 
ovoid  forms. 

The  type  of  fever  in  which  these  plasmodia  are  found,  and  which  is  now 
known  as  aestivo-autumnal  fever,  differs  very  materially  from  the  ordinary 
intermittent  (tertian  and  quartan)  fevers  met  with  in  northern  latitudes.  Under 
the  term  "aestivo-autumnal  fever"  is  included  the  majority  of  the  cases  of  so- 
called  pernicious  malarial  fevers,  and  in  this  class  of  cases,  which  are  especially 
prevalent  in  the  malarial  districts  around  Rome  where  they  studied,  Marchia- 
fava and  Celli,  in  1889,  discovered  and  described  very  minutely  the  appearance 
and  life  history  of  the  parasites  concerned  in  their  etiology.  About  the  same 
time  Canalis  published  the  results  of  his  investigations  upon  the  parasites 
associated  with  irregular  and  remittent  malarial  fevers,  and  although  his 
interpretation  of  some  of  the  phenomena  observed  differed  widely  from  those 
of  Marchiafava  and  Celli,  the  morphological  descriptions  of  the  parasites  were 
very  similar,  and  confirmed  Golgi's  theory  of  the  existence  of  a  separate  species 
of  the  malarial  parasite  causing  remittent  malarial  fever.  A  brief  summary 
of  the  investigation  of  the  above-mentioned  authors  is  here  given: 

Marchiafava  and  Celli's  observations  may  be  summed  up  as  follows:  For 
some  time  before  the  onset  of  a  paroxysm  of  fever,  three  forms  of  the  aestivo- 
autumnal  parasite  may  be  seen  in  the  blood,  i.e.,  minute  round  or  ring  forms, 
having  a  small,  dark  center,  composed  of  pigment  or  haemoglobin;  intracellular, 
minute  amoeboid,  hyalin  parasites,  containing  one  to  three  small  pigment  gran- 


EXPLANATION   OF  PLATE  II. 

Tertian  Plasmodium.       {Plasmodium  vivax.)       Stained  by  Oliver's  Modification 
of  Wright's  Stain. 

i  to  6.    "  Ring  forms  "  of  the  plasmodium. 

6.  Amoeboid,  unpigmented  form  of  the  plasmodium. 

7.  Two  "ring  forms"  in  corpuscle  showing  Schuffner's  dots. 

8.  Amoeboid  "ring  form"  in  corpuscle  showing  Schuffner's  dots. 

9  to  17.   Various  stages  in  the  development  of  the  pigmented  plasmodium. 

17.  Microgametocyte. 

1 8.  Nearly  full-grown  plasmodium,  showing  minute  division  of  the  chromatin . 

19.  20,  21.   Presegmenting  plasmodia. 
22,  23,  24.   Sporulating  plasmodia. 

25.  Microgamete.      (Flagellum.) 

26.  Sporozoites. 

Note. — With  this  stain  the  chromatin  of  the  nucleus  stains  crimson,  the  pro- 
toplasm blue,  while  the  vesicular  portion  of  the  nucleus  remains  unstained. 

Quartan  Plasmodium.      (Plasmodium  malarice.)     Same  stain  as  the  tertian  plas- 
modium. 

1  to  8.    "Ring  forms"  of  the  quartan  plasmodium. 

8  to  13.   Pigmented  forms  of  the  plasmodium.      At   11  a  so-called  "band- 
form"  is  shown. 
13,  14,  15.   Presegmenting  plasmodia. 
16,  17,  18,  19.   Sporulating  quartan  plasmodia. 

20.  Microgamete. 

21.  Sporozoites. 

Note  the  presence  of  Schuffner's  dots  in  the  infected  red  corpuscle  in  tertian 
malaria;  the  larger  size  of  the  tertian  plasmodium;  the  difference  in  the  character 
of  the  pigment,  and  the  greater  number  of  spores  or  segments. 


Plate  II 


6 


*  H 


10 


12 


ff * i   Ik'VJ* 


^U-c' 


13 


-•S  ♦'*.■•' 


15 


16 


17 


IX 


^0 


20 


21 


0 


Tertian  Plasmodium. 


•  V: 


v.1 


v.-* 


^ 


?•*• 


15 


l(i 


10 


17 


11 


■    ;  . 


IS 


@00 

Go 


19 


14 


Quartan  Plasmodium. 


C.   F.   CRAIG.   DEL. 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  33 

ules,  and  somewhat  larger  round  bodies  having  a  block  of  pigment  at  some 
portion  within  them.  The  red  corpuscles  containing  the  parasites  were  smaller 
than  the  normal  corpuscles,  darker  green  in  color,  and  crenated,  while  the 
haemoglobin  was  often  seen  to  be  retracted  from  the  periphery  of  the  corpuscle 
for  a  whole  or  part  of  its  circumference.  Segmenting  bodies  were  very  rarely 
seen  in  the  circulating  blood,  but  were  found  in  large  numbers  in  the  internal 
organs,  especially  the  spleen  and  the  capillaries  of  the  brain.  They  observed 
that  sporulation  always  occurred  before  the  onset  of  a  paroxysm,  and  that  the 
parasites  pursued  a  developmental  cycle  of  24  hours  or  less.  At  the  time  of  the 
paroxysm,  and  for  some  time  afterward,  the  small  amoeboid  hyalin  parasites, 
which  comprise  the  new  generation,  may  be  seen  in  the  blood.  They  describe 
the  crescentic  organisms  and  also  intervening  forms  between  the  intracellular 
bodies  and  the  crescents.  They  note  the  minuteness  of  the  aestivo-autumnal 
parasite  as  compared  with  the  tertian  and  quartan  forms.  They  found  the 
crescents  in  greater  number  in  the  spleen,  but  observed  many  cases  without  the 
formation  of  crescents.  No  segmentation  of  the  crescents  was  ever  noted,  and 
neither  is  the  development  of  the  pigment  always  to  be  observed.  In  those 
fevers  in  Rome  showing  daily  paroxysms  only  the  small,  hyalin,  amoeboid, 
intracellular  parasite  is  observed  in  the  peripheral  blood,  and  only  in  those 
cases  showing  a  longer  interval  between  the  paroxysms  is  the  parasite  with  the 
few  pigment  granules  to  be  observed. 

Canalis'  contribution  is  a  very  extensive  one.  He  divided  the  cycle  of 
development  of  these  parasites  into  two  phases:  a  rapid  cycle  and  a  slower  cycle 
in  which  the  crescentic  forms  appear.  The  rapid  cycle  he  considers  to  be  of 
about  two  days'  duration,  though  it  may  be  only  24  hours  in  length.  During 
the  first  hours  the  parasites  are  intracellular,  amoeboid,  hyalin,  occupying  one- 
sixth  of  the  red  corpuscle,  the  outer  portion  of  the  parasite  being  clear,  while 
the  center  appears  shaded  or  greenish,  presenting  the  appearance  of  a  nucleus. 
The  outer  portion  may  be  very  refractive.  The  blood-corpuscles  which  are 
invaded  are  very  often  smaller  than  normal  and  are  greenish  in  color.  As  the 
parasite  grows  it  becomes  more  amoeboid,  and  a  few  fine  particles  of  reddish- 
brown  pigment  may  be  seen  within  the  outer  ring-like  portion.  The  parasite 
gradually  grows  larger,  the  ring-like  appearance  disappears,  the  amoeboid  move- 
ment ceases,  the  pigment  granules  melt  into  one  small  solid  block  at  the  center 
or  one  side  of  the  parasite,  and  a  faint  radial  striation  appears,  and  from  six  to 
ten  ovoid  or  round  segments  are  eventually  produced.  They  are  much  smaller 
than  the  segments  of  tertian  or  quartan  plasmodia.  The  containing  corpuscle 
may  be  entirely  disintegrated  or  may  appear  as  a  dim,  shadowy  sphere  sur- 
rounding the  segments.  Segmenting  bodies  are  very  rarely  seen  in  the  per- 
ipheral blood,  but  free  pigment  and  pigmented  leucocytes  are  common. 

The  second,  or  slow  cycle,  in  which  cresceirts  develop,  according  to  Canalis, 
may  occur  in  connection  with  the  rapid  cycle  or  where  the  course  of  the  disease 
has  been  interfered  with  by  some  drug,  especially  quinin.  Canalis  always 
found  that  crescents  were  not  developed  until  some  time  after  the  onset  of  the 
fever,  generally  not  until  fifteen  days  had  elapsed.  The  small,  intracellular, 
amoeboid  forms  were  observed  to  become  oval  in  shape,  while  the  pigment 
collected  toward  the  center;  a  crescentic  form  was  gradually  acquired;  the  red 
corpuscle  disappeared,  and  the  now  fully  developed  crescent  was  set  free  in  the 
blood.  He  observed  the  double  outline  of  the  crescent,  and  considered  that  it 
was  due  to  an  enveloping  membrane.  The  crescents  were  afterward  observed 
to  acquire  an  oval  form  and  finally  become  perfectly  round.  In  the  crescentic 
and  ovoid  forms  the  pigment  was  always  motionless,  but  in  the  round  form  it 
often  became  very  mobile  and  was  arranged  in  a  perfect  circle.      He  describes  a 

3 


34  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

process  of  sporulation  as  occurring  in  the  crescents  and  also  observed  the  develop- 
ment of  flagellate  bodies  from  the  round  bodies,  of  which  he  says:  "They 
represent,  assuredly,  one  of  the  last  stages  in  the  development  of  the  parasite, 
for  I  have  never  seen  them  appear  in  the  blood  before  the  formation  of  the  round 
bodies."  Canal  is  considered  that  the  length  of  this  cycle  varied,  the  period 
from  the  amoeboid  stage  to  the  crescentic  lasting  from  three  to  four  days,  the 
round  bodies  taking  a  day  longer. 

In  this  truly  admirable  paper  it  is  unfortunate  that  the  author  committed 
himself  to  the  sporulation  theory  of  the  crescents,  for  in  the  light  of  our  present 
knowledge  such  a  theory  is  untenable,  unless  Schaudinn's  observations  concern- 
ing the  parthenogenesis  of  the  macrogamcte  be  confirmed. 

That  a  distinct  species  of  plasmodium  is  always  associated  with  the 
aestivo-autumnal  fevers  has  been  confirmed  by  nearly  every  student  of  the 
subject,  and  Bignami,  Sanfelice,  Plehn,  Mannaberg,  Dock,  Thayer,  Hewetson, 
and  others  have  confirmed  much  that  appeared  in  the  articles  of  Marchiafava 
and  Celli  and  Canalis.  However,  it  was  not  until  the  observations  of  Marchia- 
fava and  Bignami  were  published  that  attention  was  directed  to  the  fact  that 
two  species  of  plasmodia  are  associated  with  these  fevers  instead  of  a  single 
species.     Their  observations  are  briefly  as  follows: 

These  investigators  very  thoroughly  studied  the  parasites  occurring  in  the 
aestivo-autumnal  fevers,  and,  as  the  result  of  their  studies,  have  separated  these 
parasites  into  two  species,  one  causing  a  paroxysm  every  24  hours,  the  other 
every  48  hours,  approximately,  which  they  have  termed  the  quotidian  and 
malignant  tertian  aestivo-autumnal  parasites.  The  fever  due  to  the  quotidian 
parasite  may  be  regular  and  resemble  the  ordinary  double  tertian  curve,  but 
more  often  the  temperature  curve  shows  evidence  of  anticipation  or  retardation, 
being  irregular,  and  the  symptoms  vary  much  in  their  severity.  A  continuous 
of  slightly  remittent  fever  is  not  unusual.  The  quotidian  parasite,  as  described 
by  them,  is  a  very  small  amoeboid,  hyalin,  ring-like,  intracorpuscular  body  in 
the  peripheral  blood,  which  prior  to  segmentation  develops  a  small  number  of 
minute  pigment  granules.  Segmentation  generally  occurs  within  the  red  cell, 
and  almost  always  in  the  internal  organs,  especially  in  the  spleen.  The  rings 
are  very  pale  and  often  very  careful  search  is  required  before  they  are  dis- 
covered ;  they  are  actively  amoeboid,  and  never  exceed  one-third  of  the  corpuscle 
in  size.  The  infected  corpuscle  has  a  greenish,  brassy  color,  is  often  shrunken,  and 
the  haemoglobin  retracted.      After  some  days  crescentic  and  ovoid  bodies  appear. 

Marchiafava  and  Bignami's  malignant  tertian  parasite  produces  a  febrile 
paroxysm  lasting  practically  48  hours,  and  often  the  temperature  curve  shows 
such  variations,  caused  by  the  anticipation  and  conjunction  of  paroxysms, 
as  to  present  a  continued  fever.  According  to  them,  the  febrile  curve  presents, 
in  the  majority  of  cases,  the  following  characteristic  points:  a  rapid  and  sudden 
rise,  a  stationary  stage,  with  slight  remissions,  a  slight  pseudocrisis,  a  pre- 
critical  rise,  marked  often  by  the  highest  temperature,  and  at  last  a  sharp 
crisis  during  which  the  temperature  often  falls  far  below  normal. 

The  malignant  tertian  parasite,  as  described  by  these  authors,  resembles 
the  quotidian  very  closely,  but  is  larger  and  presents  a  greater  amount  of  pigment 
within  the  protoplasm.  It  is  often  one-half  the  size  of  the  red  corpuscle. 
Like  the  quotidian,  segmentation  occurs  mostly  within  the  vessels  of  the  internal 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  35 

organs.  The  infected  corpuscles  are  almost  invariably  shrunken,  dark  green 
in  color,  and  often  crenated  and  degenerated.  Crescents  and  ovoid  forms  appear 
after  a  few  days.  The  differences  between  the  quotidian  and  malignant  tertian 
aestivo-autumnal  plasmodia  as  given  by  Marchiafava  and  Bignami  are  as  follows : 

i.  The  length  of  the  cycle  of  development:  24  hours  in  the  quotidian  and  48 
hours  in  the  malignant  tertian  parasite. 

2.  The  larger  size  of  the  malignant  tertian  parasite  in  all  stages  of  develop- 
ment and  the  greater  amount  of  pigment  in  the  pigmented  forms  of  the  tertian 
organism. 

3.   The  greater  amoeboid  activity  of  the  malignant  tertian  parasite,  which  is 
retained  for  a  longer  period  of  time  in  the  large  pigmented  forms. 

4.  The  length  of  the  amoeboid  unpigmented  stage  which  in  the  malignant 
tertian  parasite  may  last  for  24  hours. 

Mannaberg  distinguishes  three  varieties  of  the  aestivo-autumnal  plasmodia; 
an  unpigmented  quotidian,  a  pigmented  quotidian,  and  the  malignant  tertian  para- 
site. This  classification  is  also  accepted  by  Manson,  and  Grassi  and  Feletti 
also  describe  the  pigmented  and  unpigmented  quotidian  parasites. 

In  1893  Golgi  published  an  important  paper  giving  the  results  of  his  re- 
searches regarding  the  plasmodium  of  aestivo-autumnal  infections,  in  which  he 
vigorously  combated  the  existence  of  more  than  one  variety  of  the  aestivo- 
autumnal  organism,  and  stated  that  the  forms  found  in  the  peripheral  blood 
were  chiefly  accidental,  the  infection  being  present  almost  entirely  within  the 
internal  organs. 

At  the  present  time  almost  all  authorities  who  have  studied  thoroughly  the 
aestivo-autumnal  malarial  fevers  and  who  have  had  sufficient  clinical  material 
agree  with  Marchiafava  and  Bignami  in  describing  more  than  one  species 
of  aestivo-autumnal  plasmodium;  all  accept  a  quotidian  and  tertian  variety,  and 
some  believe  that  an  unpigmented  quotidian  plasmodium  occurs  in  certain 
localities.  From  personal  observation  I  have  not  been  able  to  confirm  the 
existence  of  an  unpigmented  quotidian  organism,  but  neither  can  I  deny  it,  as 
such  infections  may  not  occur  in  the  regions  in  which  I  have  studied  malarial 
fever.  I  am  of  the  opinion,  however,  that  only  one  quotidian  plasmodium 
occurs  in  these  infections,  and  that  the  species  of  plasmodia  concerned  in  the 
etiology  of  aestivo-autumnal  malaria  are  two  in  number,  namely,  Plasmodium 
falciparum  and  Plasmodium  falciparum  quotidianum. 

The  Morphology  and  Biology  of  Plasmodium  Falciparum  Quotidi- 
anum (the  quotidian  aestivo-autumnal  parasite). — Schizogony  (human  or 
asexual  cycle). 

Unstained  Preparations. — Plasmodium  falciparum  quotidianum  completes 
its  cycle  of  development  in  man  in  twenty-four  hours,  and  appears  at  first 
within  the  red  blood-corpuscle  as  a  very  small  (0.8  to  1  micron  in  diameter) 
amoeboid,  hyalin  body,  "ring "-shaped  or  circular  in  contour,  the  trophozoite. 
In  those  individuals  which  undergo  schizogony,  the  trophozoite  quickly  becomes 
a  schizont,  enlarging  slightly  and  occupying  about  one-sixth  of  the  red  corpuscle. 
At  the  earliest  stage  of  the  quotidian  schizont  the  outline  of  the  organism  is 
very  indistinct,  and  were  it  not  for  its  active  amoeboid  motion,  it  would  be  very 
easily  overlooked.     As  the  organism  enlarges  the  outline  becomes  much  more 


6  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 


distinct.  When  fully  grown  it  is  very  clear  cut  and  the  entire  plasmodium  is 
very  refractive.  The  spherical  forms  are  perfectly  hyalin  in  appearance,  but 
the  "ring  forms"  consist  of  a  narrow  hyalin  ring  of  protoplasm  enclosing  a 
small  oval  or  circular  area  showing  the  yellowish-green  color  of  the  blood-cor- 
puscle. Most  authorities  attribute  this  appearance  to  the  fact  that  the  center  of 
the  parasite  is  much  thinner  than  the  periphery,  thus  allowing  the  normal  color 
of  the  corpuscle  to  show  through;  the  true  explanation  of  the  "ring  form" 
is  that  the  center  of  the  "ring"  is  composed  of  a  nutritive  vacuole.  When  in 
motion  the  "ring  forms"  often  appear  triangular  in  shape,  the  movement 
consisting  of  a  rapid,  wavy  motion  of  the  border  of  the  plasmodia  and  the 
shooting  out  of  minute  protoplasmic  elongations  which  are  retracted  almost 
as  quickly  as  they  are  thrown  out.  The  amoeboid  motion  is  very  rapid  and 
the  organism  has  to  be  carefully  watched  in  order  to  be  distinguished.  Some- 
times the  "ring  form"  is  lost,  the  organism  becoming  a  pale  hyaline  disk. 
The  movement  is  very  erratic,  and  there  are  long  periods  of  repose  during 
which  the  ring  form  is  retained.  The  invaded  corpuscle,  even  at  this  early 
stage  in  the  development  of  the  plasmodium,  is  generally  smaller  than  those 
which  are  normal,  presents  a  shrunken,  wrinkled  appearance,  and  is  dark 
green  in  color.  Crenation  is  often  observed  and  double  or  triple  infections  of 
the  red  cell.  The  so-called  "signet-ring"  appearance,  so  common  at  this 
stage  of  development  in  the  aestivo-autumnal  tertian  plasmodium,  does  not 
occur  in  this  species.  In  the  peripheral  blood  the  hyalin,  round,  or  ring- 
shaped  plasmodia,  just  described,  are  the  ones  commonly  observed,  although  a 
small  number  of  pigmented  forms  are  not  uncommon  in  most  cases  of  infection 
with  this  plasmodium. 

Just  prior  to  pigmentation  the  plasmodium  becomes  a  little  larger,  loses 
its  ring  form,  becomes  more  refractive  and  sharply  denned,  much  more  so  than  is 
the  malignant  tertian  plasmodium  at  the  same  stage  of  development.  In  this 
species  of  plasmodium  I  have  never  observed  a  pigmented  ring  form,  so  common 
in  the  malignant  tertian  species,  the  pigmented  bodies  always  being  oval  or 
round  in  shape  with  a  homogeneous  protoplasm.  The  pigment  appears  as  a 
single,  or  at  most  two  granules,  either  in  the  center  or  at  one  side  of  the  plas- 
modium, and  is  always  perfectly  motionless.  Sometimes  the  pigment  appears 
as  a  rather  coarse  irregular  block  situated  at  the  center  of  the  parasite,  and  such 
forms  I  consider  to  be  presegmenting  organisms.  The  pigment  is  almost 
black  in  color  and  is  never  distributed  throughout  the  protoplasm,  as  in  Plas- 
modium vivax,  or  arranged  about  the  periphery  of  the  organism,  as  in  Plas- 
modium malaria.  In  very  rare  instances  the  pigment  may  consist  of  three  or 
four  very  fine  granules,  but  they  are  always  in  intimate  association  with  one 
another.  At  this  stage  of  its  development  the  plasmodium  is  never  larger  than 
one-fourth  of  the  invaded  corpuscle,  which  is  always  shrunken,  dark  green  in 
color,  and  much  smaller  than  the  normal  red  cells.  As  a  rule,  the  invaded 
corpuscles  exhibit  marked  crenation  and  areas  of  retraction  of  the  hemoglobin. 
From  the  very  peculiar  color  of  the  invaded  cells,  they  have  been  called  "brassy 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  37 

corpuscles,"  and  it  is  in  this  form  of  malarial  infection  that  the  brassy  color 
of  the  infected  red  cell  is  most  marked. 

Segmentation  occurs  but  very  rarely  in  the  peripheral  blood,  but  may  be 
easily  observed  in  blood  obtained  by  splenic  puncture  or,  at  postmortem,  in 
blood  from  the  spleen,  liver,  brain,  and  especially  the  bone-marrow.  Segmen- 
tation occurs  at  the  end  of  twenty-four  hours,  the  plasmodium  at  this  time 
not  occupying  more  than  one-fourth  of  the  red  cell,  thus  differing  from  the 
benign  tertian  and  quartan  plasmodia  which  fill  the  corpuscle.  In  the 
segmenting  forms  the  pigment  is  collected  in  a  solid  granule  or  small  block 
at  the  center  of  the  parasite,  while  the  protoplasm  of  the  organism  appears 
slightly  granular.  As  segmentation  commences,  fine  radial  striations  can  be 
detected,  starting  from  the  center,  and  soon  the  plasmodium  breaks  up  into  from 
six  to  eight  very  minute  round  or  oval  segments,  the  merozoites.  The  beauti- 
fully regular  segmenting  forms  so  often  observed  in  quartan  infections  are  but 
rarely  observed.  Segmentation  always  occurs  within  the  red  blood-corpuscle, 
and  because  of  the  small  size  of  the  segments  and  their  limited  number,  the 
red  corpuscle  is  only  partially  filled  by  the  young  plasmodia.  Shortly  after 
segmentation  is  complete  the  red  cell  disintegrates,  thus  liberating  the  merozoites 
which  invade  normal  red  corpuscles  and  so  continue  the  infection.  As  in 
tertian  and  quartan  infections,  the  merozoites  are  of  two  kinds,  those  intended 
to  undergo  schizogony  and  those  which  undergo  sporogony.  The  forms  develop- 
ing from  the  latter  will  be  described  in  considering  the  mosquito  cycle  of  these 
parasites. 

Staining  Reactions  of  Plasmodium  Falciparum  Quotidianum. — 
As  the  staining  reactions  of  this  species  of  plasmodium  are  identical  in  large 
measure  with  those  of  Plasmodium  falciparum,  I  will  describe  them  in  dealing 
with  the  latter  organism. 

Morphology  and  Biology  of  Plasmodium  Falciparum. — (The  tertian 
aestivo-autumnal  parasite.  Malignant  tertian  or  subtertian  parasite  of  some 
authors.)    Schizogony  (human  or  asexual  cycle). 

This  is  the  most  common  species  of  aestivo-autumnal  plasmodium  and  is 
the  one  which  has  been  most  frequently  observed  and  studied.  The  majority 
of  infections  with  aestivo-autumnal  malaria  are  due  to  this  parasite,  and  even  in 
those  limited  regions  where  the  quotidian  plasmodium  has  been  observed  the  lat- 
ter is  very  rare  in  comparison  with  the  tertian  species.  In  many  instances  of  quoti- 
dian aestivo-autumnal  infection  a  combined  infection  exists  with  the  malignant 
tertian  plasmodium  and  this  has  caused  much  confusion  in  the  description 
which  have  been  given  of  the  aestivo-autumnal  plasmodia  by  various  observers. 
In  those  cases,  however,  in  which  the  two  organisms  occur  alone,  they  may 
be  readily  differentiated  by  their  morphological  characteristics  and  their  cycle 
of  development. 

Unstained  Preparations. — Like  the  quotidian  species,  the  tertian  aestivo- 
autumnal  plasmodium,  or  Plasmodium  falciparum,  appears  first  within  the 
infected  red  corpuscle  as  a  round  or  oval  hyalin  ring  or  disk,  but  even  in  the 


3©  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

earliest  stage  of  development  of  the  scJiizont  important  differences  are  to  be 
noted  between  this  and  the  quotidian  species.  The  young  tertian  plasmodia 
are  considerable  larger  than  those  of  the  quotidian  species,  occupying  from 
one-quarter  to  one-third  of  the  infected  red  cell,  which,  while  smaller  than 
the  normal  cells  surrounding  it,  and  greenish  in  color,  is  not  shrunken  and 
wrinkled  at  this  early  stage  of  development  as  in  quotidian  infections.  The 
''ring  forms"  are  irregular  in  outline,  one  portion  of  the  "ring"  being  broader 
than  the  remainder,  giving  rise  to  the  so-called  "signet-ring"  appearance, 
never  observed  in  quotidian  infections.  The  organism  is  more  highly  refractive 
and  sharply  outlined,  and  the  amoeboid  motion  is  more  sluggish  and  more 
easily  observed.     The  ring  form  is  often  lost,  a  clear,  hyalin  disk  resulting. 


Fig.  9. — Plasmodium  falciparum  tertianum.     (Aestivo-autumnal  tertian.)     Two  "ring 
forms"  and  two  young  gametes.     Photomicrograph,    X  1200. 


Very  rarely  is  more  than  one  parasite  seen  in  a  single  corpuscle,  except  when 
intracorpuscular  conjugation,  a  process  common  to  all  malarial  plasmodia, 
is  present.  The  changes  in  the  outline  of  the  plasmodium  are  very  marked, 
and  it  is  much  more  easily  recognized  than  is  the  quotidian  plasmodium 
(see  Fig.  9). 

In  the  course  of  from  20  to  24  hours  the  hyalin  forms  become  pigmented, 
the  pigment  occurring  in  the  form  of  very  fine,  reddish-brown  granules  some- 
what resembling  those  found  in  the  benign  tertian  plasmodium.  The  pigment 
is  in  larger  amount  than  in  the  quotidian  plasmodium,  is  sluggishly  motile,  and 
makes  its  appearance  while  the  plasmodia  are  ring-shaped,  being  situated 
within  the  enlarged  area,  thus  giving  the  organisms  a  still  greater  resemblance 
to  a  signet  ring.     The  organism  gradually  loses  the  ring-form  and  becomes 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  39 

larger,  sometimes  filling  one-half  of  the  corpuscle;  at  the  same  time  it  becomes 
more  clearly  defined,  its  protoplasm  more  refractive  and  faintly  granular  in 
appearance.  The  amoeboid  motion  still  continues,  though  very  sluggishly,  and 
the  pigment  tends  to  collect  in  a  solid  block,  which  has  a  marked  vibratory 
movement.  The  pigmented  form  is  more  common  in  the  peripheral  blood 
than  is  the  pigmented  form  of  the  quotidian  plasmodium,  but  is  rare  as  com- 
pared with  the  tertian  or  quartan  pigmented  forms. 

In  this  plasmodium  segmentation  occurs  at  the  end  of  48  hours  in  the  vast 
majority  of  infections,  although  rarely  segmentation  may  occur  two  or  three 
hours  earlier.  At  this  time  the  plasmodium  has  grown  to  be  one-half  to  two- 
thirds  as  large  as  the  red  corpuscle,  the  pigment  has  become  motionless  and 
collected  in  a  solid  block  near  or  at  the  center,  and  distinct  radial  striations  are 
visible  starting  from  the  center  of  the  organism,  dividing  it  into  from  10  to  15 
segments  or  merozoites.  In  some  instances  as  many  as  24  merozoites  have  been 
counted.  The  merozoites  are  larger  than  those  of  the  quotidian  species,  are 
oval  in  shape,  and  appear  very  refractive.  Segmentation  occurs  within  the  red 
blood-corpuscle,  but  its  situation  is  not  so  easy  to  distinguish  in  this  species  as  in 
the  quotidian.  The  sporulating  forms  occur  very  rarely  in  the  peripheral 
blood,  and  I  have  observed  but  one  case  in  which  such  forms  occurred  in  blood 
removed  from  the  peripheral  circulation  in  the  thousands  of  cases  of  tertian 
aestivo-autumnal  infection  which  I  have  studied. 

The  young  merozoites  are  liberated  in  the  blood  plasma  by  the  disintegra- 
tion of  the  red  blood-corpuscle  and  infect  normal  red  cells,  thus  continuing  the 
human  cycle  of  the  plasmodium.  Besides  the  merozoites  which  continue  the 
human  cycle  of  development  there  are  others  which  enter  ihe  red  corpuscles 
and  develop  into  gametes,  thus  rendering  possible  the  infection  of  the  mosquito. 

Staining  Reactions  of  Plasmodium  Falciparum  and  Falciparum 
Plasmodium  Quotidianum. — The  staining  reactions  of  these  two  species 
of  malarial  plasmodia  are  similar  in  most  respects  to  the  staining  reac- 
tions of  the  benign  tertian  and  quartan  plasmodia,  when  Wright's  method  of 
staining  is  employed.  These  plasmodia  are  seen  to  consist,  in  the  unpig- 
mented  and  early  pigmented  stages,  of  a  ring  of  blue-stained  protoplasm  sur- 
rounding a  large  nutritive  vacuole,  at  one  side  of  which  is  situated  a  small, 
vesicular,  milky  appearing  nucleus  containing  one  or  two  small  masses  of 
chromatin  stained  a  deep  red  or  violet.  In  the  aestivo-autumnal  "rings"  the 
chromatin  is  often  seen  to  project  outward  from  the  periphery  of  the  blue- 
stained  ring  of  protoplasm,  an  appearance  never  observed  in  Plasmodium 
vivax  and  Plasmodium  malariae.  The  blue-stained  protoplasm  in  the  quotidian 
ring  forms  is  very  small  in  amount,  forming  a  very  delicate  thin  ring,  while  in 
the  malignant  tertian  plasmodium  the  blue-stained  protoplasm  is  thicker  and  at 
one  portion  of  the  circumference  of  the  ring  spreads  out  into  a  very  definite 
enlargement  in  which  the  pigment,  if  it  be  present,  is  generally  situated. 

Changes  in  the  Infected  Red  Blood-corpuscles. — I  have  already 
described  the  changes  observed  in  the  infected  red  blocd-corpuscles  in  tertian 


40  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

and  quartan  malarial  fevers.  It  will  be  remembered  that  in  infections  with 
Plasmodium  vivax,  the  invaded  red  corpuscle  enlarges,  becomes  pale,  and  a 
peculiar  form  of  degeneration  occurs  which  results  in  the  appearance  in  stained 
specimens  of  the  so-called  Schuffner's  dots;  while  in  infections  with  Plasmodium 
malariac  the  invaded  red  cells  generally  became  slightly  smaller,  deeper  green  in 
color,  and  stained  specimens  show  the  absence  of  Schuffner's  dots.  The  red 
blood-corpuscles  when  invaded  by  either  species  of  the  aestivo-autumnal 
Plasmodia  become  much  smaller  than  the  normal  red  corpuscles,  and  much 
darker  green  in  color.  In  infections  with  the  quotidian  species  the  red  cells  are 
greatly  shrunken,  appear  wrinkled,  are  brassy  in  color,  and  are  almost  always 
much  crenated;  in  infections  with  the  malignant  tertian  plasmodium  these 
changes  are  not  so  marked,  the  red  cell  being  smaller  than  normal,  but  seldom 
presenting  a  wrinkled  appearance,  and  is  less  often  crenated.  Brassy  appear- 
ing corpuscles  are  very  common,  however,  in  malignant  tertian  infections, 
although  the  reduction  in  the  size  of  the  red  corpuscle  is  less  marked  than  in 
infections  with  the  quotidian  plasmodium.  In  neither  type  of  infection  do  the 
invaded  red  cells  show  the  presence  of  Schuffner's  dots,  although  many  of  them 
present  deeply  stained,  bluish  granules,  which  have  been  called  Marshall's 
dots  or  granules  by  some  authorities,  and  which  are  undoubtedly  due  to  some 
form  of  degeneration  of  the  cytoplasm  of  the  cells,  caused  by  the  aestivo-autum- 
nal plasmodia. 

So  far  as  the  changes  in  the  infected  red  blood-corpuscles  are  concerned, 
the  aestivo-autumnal  plasmodia  resemble  the  quartan  plasmodium  rather  than 
the  benign  tertian,  but  in  the  aestivo-autumnal  infections  the  invaded  red 
corpuscles  are  much  smaller  than  are  the  corpuscles  infected  with  Plasmodium 
malariae  and  much  deeper  green  in  color,  while  the  wrinkling  and  crenation  of 
the  corpuscles,  so  common  in  aestivo-autumnal  infections,  especially  the 
quotidian,  are  very  seldom  if  ever  observed  in  the  cells  invaded  by  the  quartan 
plasmodium. 

The  Sporogenic  Forms  of  the  Malarial  Plasmodia  Occurring  in 
Human  Blood. — I  have  so  far  described  the  forms  of  the  various  species  of 
malarial  plasmodia  occurring  in  the  blood  of  man  which  are  concerned  in 
schizogony  only,  but  there  occur  other  forms  which  do  not  sporulate  in  human 
blood  and  which  are  intended  to  continue  the  existence  of  the  malarial  plasmo- 
dia in  mosquitoes.  It  is  a  question  whether  these  latter  forms,  which  may  be 
called  sporogenic  forms  as  they  are  concerned  in  sporogony,  are  introduced  into 
the  blood  of  man  by  the  bite  of  the  infected  mosquito  or  whether  they  are 
elaborated  during  the  development  of  the  plasmodia  in  human  blood.  By 
some  it  is  considered  that  the  sporozoites  introduced  by  the  infected  mosquitoes 
are  of  two  varieties,  those  which  develop  into  schizonts  and  those  which  develop 
into  gametes,  while  other  authorities  believe  that  all  of  the  sporozoites  injected  by 
the  mosquito  develop  into  schizonts,  and  that  after  a  certain  period  of  time  certain 
of  the  merozoites  produced  by  the  sporulation  of  the  schizonts  become  differen- 
tiated into  forms  which  develop  into  gametes.     According  to  Schaudinn,  the 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  41 

stimulus  to  the  production  of  the  gametes  or  sporonts  is  due  to  the  reaction  of  the 
host,  man,  upon  the  plasmodium,  and  that  such  forms  occur  only  after  the 
infection  has  lasted  for  some  time  appears  to  be  conclusive  proof  of  this  theory. 
Personally,  I  believe  with  Schaudinn  that  the  gametes  are  produced  only  after 
the  plasmodia  have  undergone  sporulation  for  some  time,  and  that,  therefore, 
they  are  of  human  origin,  being  differentiated  during  the  process  of  schizogony, 
and  not  introduced  as  such  by  the  infected  mosquito.  In  other  words,  all  of  the 
sporozoites  introduced  by  the  insect  develop  into  schizonts,  the  gametes  or 
sporonts  developing  from  the  schizonts  after  a  certain  time,  some  of  the  merozoites 
being  thus  differentiated.  The  development  of  the  merozoites  into  gametes  is 
much  slower  than  into  schizonts,  taking,  according  to  Schaudinn,  twice  as  long. 
In  his  work  upon  Plasmodium  vivax  he  found  that  the  development  of  the 
gamete  from  the  merozoite  took  96  hours,  while,  as  is  well  known,  the  develop- 
ment of  the  merozoite  into  the  sporulating  schizont  occupies  only  48  hours. 
Ruge  does  not  agree  with  Schaudinn  in  this,  but  believes  that  the  gametes 
develop  coincidently  with  the  sporulating  schizonts,  and  that  the  majority  of  the 
gametes  perish  during  apyrexia.  I  cannot  agree  with  the  theory  of  Ruge  for  it 
is  well  known  that  the  gametes  (crescents)  of  aestivo-autumnal  fever  may  exist 
for  months  in  the  blood,  during  which  time  apyrexia  has  been  practically 
constant. 

The  gametes  are  invariably  of  two  kinds,  male  and  female.  They  can  be 
differentiated  from  one  another  and  occur  in  varying  proportions,  the  male 
organisms  being  the  most  numerous.  Stephens  and  Christophers  found 
in  aestivo-autumnal  infections,  53  micro gametocytes  (males)  to  2>3  macro- 
gametes  (females),  but  Ruge  found,  in  benign  tertian  infections,  that  the 
proportion  varied  very  greatly  in  different  cases,  some  infections  showing 
equal  numbers  of  male  and  female  gametocytes,  while  in  others  he  found  only 

1  micro  gametocyte  to  50  macro  gametes.  It  is  very  probable  that  the  proportion 
varies  somewhat  in  every  case,  due  to  the  conditions  favoring  development 
brought  about  by  the  reaction  of  the  system  to  infection. 

The  differentiation  of  the  intracellular  gametes  from  the  schizonts  is  not 
difficult  in  most  instances,  if  the  following  morphologic  data  be  remembered: 

1.  Absence  of  "ring  form"  in  all  cases,  the  chromatin  in  the  youngest 
stage  or  trophozoite,  being  situated  in  the  center  of  the  organism,  surrounded 
by  the  protoplasm.  Thus  there  is  an  absence  of  the  nutritive  vacuole  which 
produces  the  ring  like  appearance  in  this  stage  of  the  schizont. 

2.  The  cytoplasm  in  the  male  gamete  is  more  dense,  and  stains  a  deeper 
blue,  than  in  the  schizont,  while  in  the  female  gametes  it  is  less  dense  and  stains 
very  faintly. 

3.  The  pigment  is  larger  in  amount  in  the  gametes  and  more  rod-like  in 
form  or  in  larger  granules. 

4.  In  benign  tertian  and  in  quartan  infections  the  mature  intracellular 
gametes  are  larger  than  the  mature  schizonts,  there  being  a  difference  of  from 

2  to  6  microns  in  the  diameter  of  the  organisms. 


42  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

5.  In  aestivo-autumnal  infections  the  gametes  are  crescentic  in  form  and 
are  thus  easily  distinguished  from  the  full-grown  schizont. 

Ruge  states  that  any  small  unpigmented  plasmodium  showing  the  chroma- 
tin situated  within  the  blue-stained  protoplasm,  with  no  unstained  area  between 
it  and  the  protoplasm,  should  be  considered  as  a  gamete.  Maurer  describes 
the  young  gamete  as  circular  in  form,  and  composed  of  a  broad,  blue-stained 
band,  enclosing  a  small  amount  of  achromatic  substance  in  which  lies  a  large 
granule  of  bright  red  chromatin.  In  very  deeply  stained  specimens  a  thick 
deep  red  border  surrounds  the  organism,  which  is  especially  prominent  in  the 
crescentic  gametes.  As  growth  proceeds  the  disk  form  is  lost,  the  achromatic 
substance  disappears,  the  chromatin  becomes  broken  up  into  small  threads, 
and  very  coarsely  granular  pigment  is  developed.  In  the  crescentic  gametes 
a  deep  red  border  is  observed  surrounding  them,  which  Maurer  calls  the 
capsule  of  the  crescent.  Maurer's  description  applies  to  specimens  stained 
by  Romanowsky's  method,  and  I  have  confirmed  all  that  he  says  many  times 
in  specimens  stained  by  the  method  of  Wright. 

Schaudinn  claims  that  in  benign  tertian  infections,  the  male  gametes  or 
micro gametocytes  gradually  disappear  after  the  attack  of  fever  has  ceased,  until 
in  from  three  to  six  weeks  only  the  female  gametes  or  macro  gametes  can  be 
found  in  the  blood.  I  have  not  found  that  this  is  the  case  in  aestivo-autumnal 
malaria,  for  in  such  infections  I  have  observed  both  male  and  female  gametes 
in  the  blood  for  weeks  after  the  active  symptoms  had  ceased,  and  in  practically 
the  same  numbers  during  the  entire  period  of  observation. 

In  considering  the  forms  of  the  malarial  plasmodia,  which  may  be  observed 
in  the  blood  of  man,  and  which  are  intended  to  undergo  development  within 
mosquitoes  belonging  to  the  Anophelinae,  we  have  to  consider,  for  each  species 
of  plasmodium,  the  gametes  in  general,  and  the  macrogamete,  the  microgame- 
tocyte,  and  the  micro  gamete  in  particular.  The  development  of  these  forms 
will  be  considered  in  the  next  chapter  of  this  work. 

The  Sporogenic  Forms  of  Plasmodium  Vivax  Occurring  in  the 
Blood  of  Man. — In  the  study  of  the  blood  of  benign  tertian  cases  it  will  be 
observed  that  a  certain  number  of  the  fully  developed  pigmented  plasmodia 
do  not  sporulate,  but  become  free  in  the  blood  as  spherical  bodies  which  are  of 
two  kinds,  those  which  produce  flagella  or  microgametes,  and  which  are  called 
micro  gametocytes,  and  those  which  do  not  form  flagella,  which  are  called 
macrogametes.  The  first  are  the  male  organisms,  the  second  the  female.  In 
the  stomach  of  the  mosquito  the  microgametes,  liberated  from  the  micro- 
gametocyte,  penetrate  and  fertilize  the  macrogametes,  thus  producing  a  sporont. 
In  very  rare  instances  this  process  of  fertilization  may  be  observed  in  blood 
which  has  been  removed  from  the  body  for  some  time,  and  it  is  very  common 
to  observe  the  process  of  flagellation,  as  it  is  called,  and  the  liberation  of  the 
flagellum  or  micro  gamete.  In  fresh  specimens  of  tertian  blood,  the  gametes 
cannot  be  distinguished  until  they  are  fully  developed,  but  in  stained  specimens 
they  can  be  distinguished  without  much  difficulty  in  all  stages  of  development. 


EXPLANATION  OF  PLATE  III. 

Quotidian    Aestivo-autumnal    Plasmodium.      {Plasmodium   falciparum  quotidi- 
anum.)      Stained  with  Oliver's  Modification  of  Wright's  Stain, 
i  to  ii.    "Ring  forms"  of  the  quotidian  Plasmodium. 
ii,  12.   Pigmented  forms  of  the  quotidian  Plasmodium. 

13.  Presegmenting  Plasmodium. 

14.  Sporulating  plasmodium. 
1  5.   Microgametocyte. 

16.   Macrogametes. 
Chromatin,  red;  protoplasm,  blue;  vesicular  portion  of  nucleus,  unstained. 

Tertian  Aestivo-autumnal  Plasmodium.     (Plasmodium  falciparum.)     Same  stain. 
1,  2.   "Ring  forms"  of  the  tertian  aestivo-autumnal  plasmodium. 

3.  Pigmented  "ring  form." 

4,  5,  6,  7.   Pigmented  forms  of  the  plasmodium. 

8.  Young  gamete. 

9.  Nearly  full-grown  form,  showing  peculiar  chromatin  border. 

10.  Full-grown  form. 

11,  12.    Sporulating  pla  modia. 

13.  Microgametocyte. 

14.  Macrogamete. 

Group  A.      Gametes  of  Plasmodium  Vivax.      (Tertian  plasmodium.) 

1.  Young  microgametocyte. 

2,  3.   Fully  grown  microgametocytes. 

4.  Young  macrogamete 

5,  6.   Fully  grown  macrogametes. 

7.  Extracellular  macrogamete. 

8.  Flagellated  microgametocyte. 

Group  B.      Gametes  of  Plasmodium  malaria.      (Quartan  plasmodium.) 

1.  Young  microgametocyte. 

2,  3.   Fully  grown  microgametocytes. 

4,  Young  macrogamete. 

5,  6.   Fully  grown  macrogametes. 

7.  Extracellular  macrogamete. 

8.  Flagellated  microgametocyte. 

Group    C.     Gametes    of   Plasmodium   falciparum.      (Tertian    aestivo-autumnal 
Plasmodium.) 

1.  Young  gamete. 

2.  Microgametocyte. 

3.  Macrogamete. 

4.  5.   Microgametocytes.      (Crescents.) 

6,  7.   Macrogametes.      (Crescents.) 

8.  Ookinetes. 

9.  Sporozoites. 


Plate  III 


i 


4        I  Q 


ft 


10  11  12  13  14  15 

Quotidian  Aestivo-autumnal  Plasmodium. 


/■'"' 
(1^ 


/* 
O 


G 

2 


# 


jtf& 


■i*i- 


A   4* 


12 


14 


Tertian  Aestivo-autumnal  Plasmodium. 


0 


1    '^2  ^I3 


Group  A. 


3 


V&P  6 


Group  B. 


Group  C. 


C.    F.   CRAIG.   DEL. 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  43 

Fresh  Preparations. — The  Gametes. — In  fresh  specimens  of  blood  the 
gametes  of  Plasmodium  vivax  cannot  with  certainty  be  distinguished  as  such 
until  they  are  fully  developed  and  liberated  in  the  blood  plasma  by  the  disin- 
tegration of  the  red  cell  in  which  they  have  developed.  At  this  time  they  can 
be  easily  differentiated  into  two  forms,  the  macrogamete  and  the  micro- 
gametocyte. 

The  Macrogamete. — The  tertian  macrogamete  is  a  large,  pigmented 
organism,  measuring  from  9  to  11  microns  in  diameter;  the  protoplasm  appears 
slightly  granular,  and  the  pigment  is  in  the  form  of  large  granules  or  clumps, 
arranged  about  the  periphery  of  the  organism,  or  commonly  in  a  wreath-like 
form  some  distance  from  the  periphery.  The  pigment  is  not  motile,  and 
exflagellation  never  occurs  in  the  forms  presenting  this  arrangement  of  the 
pigment  granules.  In  rare  instances  a  flagellum  may  be  seen  attached  to  the 
circumference  of  the  macrogamete,  and  such  an  appearance  always  indicates  an 
attempt  at  fertilization,  and  may  be  observed  in  the  blood  much  more  fre- 
quently than  is  generally  supposed.  Sometimes  more  than  one  flagellum  or 
micro  gamete  may  be  seen  attached  to  the  macrogamete,  and  their  movements 
are  peculiar  and  characteristic.  Instead  of  the  rapid  serpentine  lashings  seen 
in  the  microgametes,  when  attached  to  the  micro gametocyte,  the  movements 
are  of  an  entirely  different  character.  The  microgametes  appear  to  straighten 
and  then  relax,  revolving  apparently  very  rapidly  upon  their  axes;  sometimes 
they  may  be  seen  to  pull  themselves  loose  from  the  macrogamete  and  again 
become  attached  to  it.  In  the  meanwhile  the  pigment  within  the  macrogamete 
has  maintained  its  circular  arrangement,  and  is  at  most  very  slowly  motile. 
The  movements  observed  are  produced  by  the  efforts  of  the  microgamete  to 
penetrate  the  macrogamete,  a  process  which  normally  occurs  within  the  stomach 
of  the  mosquito. 

The  Microgametocyte. — The  micro  gametocyte  of  Plasmodium  vivax 
measures  from  8  to  10  microns  in  diameter,  is  spherical  in  outline  when  fully 
developed,  and  free  in  the  blood  plasma,  and  contains  a  large  amount  of  pigment 
in  the  form  of  large  and  small  granules,  distributed  throughout  the  protoplasm. 
When  first  liberated  from  the  red  blood-corpuscle  in  which  it  has  developed, 
the  pigment  is  sluggishly  motile,  but  in  those  micro  gametocytes  in  which  micro- 
gametes are  developing,  the  pigment  soon  becomes  very  actively  motile,  much 
more  so  than  in  any  other  form  of  malarial  plasmodium,  while  the  protoplasm 
of  the  organism  also  appears  to  be  in  motion,  marked  undulations  of  the 
periphery  being  often  apparent.  In  those  instances  in  which  the  pigment  is 
immotile  it  is  collected  in  small,  irregular  clumps  throughout  the  protoplasm 
instead  of  about  the  periphery  or  in  a  wreath-like  arrangement,  as  in  the 
macrogamete.  If  a  micro  gametocyte  in  which  the  pigment  is  in  active  motion 
be  watched,  in  a  variable  length  of  time, — from  five  minutes  to  half  an  hour  or 
more-  -the  pigment  will  be  seed  to  collect  toward  the  center  of  the  protoplasm, 
the  motility  becoming  somewhat  lessened,  and  suddenly,  as  though  an  explosion 
had  occurred  within  the  organism,  there  appear  at  certain  portions  of  the 


44  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

periphery  long,  thin,  colorless,  thread-like,  actively  moving  filaments,  which 
vary  in  number  from  two  to  six,  and  which  undulate  rapidly,  lashing  about 
among  the  red  corpusles  to  which  they  often  impart  a  perculiar  spinning  motion. 
These  filaments  are  the  micro  gametes. 

There  may  now  occur  one  of  several  things:  either  the  microgametes  may 
break  loose  from  the  parent  plasmodium,  which  is  the  normal  procedure,  or, 
unable  to  do  so,  may  become  motionless  and  degenerate,  or  the  micro gametocyte 
may  undergo  degeneration  before  the  microgametes  have  succeeded  in  freeing 
themselves.  In  the  first  instance,  after  the  microgamete  has  lashed  about  among 
the  red  blood-corpuscles  for  a  variable  length  of  time,  seemingly  trying  to  free 
itself  from  the  micro  gametocyte,  it  at  last  succeeds,  and  moves  off  in  a  serpentine 
manner  among  the  red  cells.  In  some  instances  the  efforts  of  the  microgamete 
to  free  itself  are  very  vigorous,  resulting  in  its  pulling  the  micro  gametocyte  about 
for  appreciable  distances  in  the  microscopic  field.  After  it  becomes  free  the 
serpentine  motion  may  be  retained  for  a  long  time,  even  an  hour  or  more.  If  it 
chances  that  only  a  single  microgamete  arises  from  the  micro  gametocyte,  the 
latter  quickly  degenerates  after  the  liberation  of  the  microgamete. 

In  those  instances  in  which  the  microgametes  are  unable  to  free  them- 
selves from  the  plasmodium,  after  a  time  they  become  motionless,  and  the 
entire  organism  shrinks,  becomes  vacuolated,  and  finally  disintegrates.  In 
rare  instances  the  micro  gametocyte  undergoes  degeneration  before  the  micro- 
gametes are  extruded  or  before  they  are  able  to  free  themselves  from  the  parent 
body;  in  such  instances  the  micro  gametocyte  undergoes  fragmentation,  each 
fragment  containing  pigment.  Careful  observation  will  show  that  these  frag- 
ments remain  attached  to  one  another  for  a  long  time  by  very  delicate  threads 
of  protoplasm;  if  microgametes  have  developed  before  fragmentation,  they 
become  motionless  and  disintegrate,  but  the  fragments  containing  the  pigment 
may  persist  for  a  long  time,  and  have  been  mistaken  for  new  parasites  of  the 
blood.  In  one  instance  the  pigment  in  one  of  these  fragments  was  observed  to 
be  in  active  motion  after  a  period  of  eight  hours  at  room  temperature. 

The  microgametocyte,  after  the  microgametes  have  been  liberated,  quickly 
degenerates,  either  becoming  vacuolated,  or  breaking  up  into  small  spherical 
bodies  containing  pigment.  Not  infrequently  the  entire  organism  remains  as 
an  irregular  mass  of  cytoplasm  containing  the  pigment  in  the  form  of  irregular 
clumps  collected  toward  the  center,  and  absolutely  motionless. 

The  Microgametes. — In  fresh  specimens  of  blood  the  tertian  microgamete 
appears  as  a  very  slender,  thread-like  body,  perfectly  colorless,  and  having  a 
serpentine,  undulating  motion,  enabling  it  to  progress  among  the  blood-corpuscles 
which  are  displaced  or  moved  about  by  its  motions.  A  careful  study  of  micro- 
gametes shows  that  considerable  variations  occur  in  individual  specimens  as 
regards  appearance.  I  have  already  spoken  of  the  variation  in  number  and  of 
the  manner  in  which  they  free  themselves  from  the  microgametocyte.  While 
still  attached  to  the  latter  they  often  present  a  clubbed  extremity,  which  changes 
its  form,  sometimes  appearing  blunt,  sometimes  pointed;  after  liberation  of  the 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  45 

organism  the  extremities  both  appear  pointed,  and  are  difficult  to  distinguish. 
The  micro  gametes  measure  from  two  to  four  times  the  diameter  of  the  micro- 
gametocyte,  but  it  is  not  uncommon  to  observe  micro  gametes  that  are  from  five 
to  eight  times  as  long  as  the  diameter  of  the  parent  organism.  Besides  the 
clubbed  extremity  that  is  often  present,  the  microgametes  sometimes  show  small 
nodular  swellings  along  their  course  in  which  are  a  few  pigment  granules 
derived  from  the  body  of  the  micro gametocyte.  After  liberation  the  micro- 
gametes  appear  to  extrude  this  pigment  and  at  the  time  they  fertilize  the  macro- 
gametes  they  are  entirely  hyaline  in  appearance.  In  rare  instances  short,  very 
thick  forms  are  observed,  which  have  a  very  sluggish  serpentine  motion. 

Stained  Preparations. — In  stained  preparations  of  blood  infected  with 
Plasmodium  vivax  all  stages  in  the  development  of  the  gametes  can  be  easily 
recognized.  During  their  intracorpuscular  development  they  can  be  distin- 
guished from  the  schizonts  during  the  trophozoite  phase  somewhat  more  easily 
than  during  later  stages  of  development,  but  after  they  have  become  extracor- 
puscular  they  can  be  distinguished  without  difficulty  in  nearly  every  instance  of 
infection.  The  merozoites  which  are  destined  to  develop  into  gametes  cannot  be 
differentiated  even  in  stained  preparations,  from  those  destined  to  become 
schizonts. 

The  Gametes. — The  gametes  of  Plasmodium  vivax,  in  their  earliest  stage 
of  development,  when  stained  by  Wright's  method,  consist  of  a  perfectly  circular 
mass  of  blue-stained  protoplasm,  in  the  center  of  which  is  a  spherical  dot  of  chro- 
matin stained  a  deep  red  or  violet.  The  achromatic  zone,  or  nutrient  vacuole, 
which  gives  the  "ring"  appearance  to  the  young  schizont,  is  not  present  in  the 
trophozoites  which  become  gametes,  and  the  organism  at  this  stage  of  develop- 
ment is  larger  than  is  the  schizont.  In  those  gametes  which  have  become  pig- 
mented, the  pigment  is  greater  in  amount  than  in  the  schizonts,  and  is  distributed 
throughout  the  protoplasm.  In  such  gametes  the  protoplasm  stains  blue  and 
the  chromatin,  which  is  arranged  in  fibrils  throughout  the  protoplasm,  stains  a 
pinkish  red,  and  is  not  collected  in  masses  at  any  stage  in  the  development  of  the 
gamete  while  it  is  intracorpuscular.  The  gametes  are  always  circular  in  shape 
at  every  stage  of  intracorpuscular  development. 

The  following  observations  are  of  diagnostic  importance  in  differentiating 
the  benign  tertian  gametes  from  the  schizonts. 

1.  The  gamete  is  larger  throughout  its  development  than  is  the  schizont. 

2.  It  is  much  less  amoeboid,  and,  therefore,  is  circular  in  contour  in  every 
stage  of  development  in  the  red  corpuscle. 

3.  No  nutritive  vacuole  is  present  in  the  young  gametes,  and  thus  they  are 
not  "ring-like"  in  form.  In  stained  preparations  there  is  no  achromatic  zone 
surrounding  the  chromatin  dot  as  in  the  schizont. 

4.  The  gametes  show  very  little  amoeboid  motion  at  any  stage  of  their 
development. 

5.  The  pigment  in  the  gametes  is  much  greater  in  amount  and  earlier 
developed  than  in  the  schizonts.     It  is  present  in  almost  the  earliest  forms,  and 


46  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

in  the  fully  developed  gamete  is  still  motile,  while  it  is  motionless  in  the  fully 
grown  schizont. 

6.  The  chromatin  divides  earlier  in  the  gamete  than  in  the  schizont,  is 
loosely  arranged,  and  never  separates  into  distinct  masses. 

7.  The  period  of  development  within  the  red  corpuscle  is  almost  twice  as 
long  for  the  gamete  as  for  the  schizont;  hence  the  greater  amount  of  pigment  in 
the  former  and  its  larger  size. 

After  development,  the  gametes,  if  they  are  not  ingested  by  mosquitoes, 
degenerate,  and  disappear  after  some  weeks,  although  Schaudinn  claims  that 
the  female  gamete  or  macrogamete,  under  such  circumstances,  may  undergo  par- 
thenogenesis and  thus  produce  new  generations  of  schizonts,  leading  to  a  relapse 
of  the  infection. 

In  stained  specimens  the  gametes  may  be  differentiated  into  male  and 
female  forms,  the  micro  gametocytes  and  the  macro  gametes. 

The  Macrogametes.  (Female  gametes.)  In  stained  specimens  the  proto- 
plasm of  the  macrogametes  stains  an  intense  blue,  much  darker  than  does  the 
protoplasm  of  the  schizonts.  The  nuclear  chromatin  is  small  in  amount  at  all 
stages,  consisting  in  the  earliest  stage  of  development  of  a  minute  dot  and  later 
of  a  few  small  dots  or  rods  situated  near  the  periphery  of  the  organism,  stained  a 
bright  red  in  color.  The  pigment  is  very  dark,  almost  black  in  color,  and  is  in 
the  form  of  large  rods,  as  much  as  1  to  3  microns  in  length,  in  the  fully  developed 
macrogametes.  It  is  very  sluggish  in  motion  and  is  apt  to  be  collected  in  ir- 
regular masses  toward  the  periphery  or  the  center  of  the  organism.  It  is  very 
often  observed  arranged  in  a  wreath-like  manner  close  to  the  border  of  the 
organism.     The  macrogametes  are  always  circular  in  contour. 

The  macrogametes  may  be  distinguished  from  the  micro  gametocytes  by: 

1.  In  the  fresh  specimen,  a  granular  protoplasm  containing  much  nutrient 
material,  visible  as  large  refractive  granules.  When  stained,  by  the  dark  blue 
color  of  the  protoplasm. 

2.  The  macrogamete  has  a  smaller  amount  of  nuclear  chromatin,  sometimes 
only  a  few  dots,  situated  about  the  periphery  of  the  organism. 

3.  A  longer  period  of  development  and  greater  persistence  in  the  blood  of 
man  after  the  active  symptoms  of  malaria  have  ceased. 

4.  Larger  size,  measuring  from  13  to  16  microns. 

5.  Darker  colored  pigment,  consisting  of  large  rods  measuring  from  1  to  3 
microns  in  length.  The  benign  tertian  macrogamete  is  the  only  form  of  the 
malarial  plasmodia  presenting  such  large  rods  of  pigment. 

6.  Less  active  movement  of  the  pigment  and  its  arrangement  in  a  wreath- 
like formation. 

The  Microgametocytes. — The  micro  gametocytes  of  Plasmodium  vivax,  in 
their  various  stages  of  development,  differ  somewhat  in  the  appearances  they 
present  in  stained  specimens.  During  their  earliest  intracorpuscular  stage  they 
are  distinguished  from  other  forms  by  the  pale  blue  staining  of  their  protoplasm, 
which,  in  the  larger  forms,  sometimes  appears  hyaline  even  in  stained  prepara- 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  47 

tions.  The  chromatin  is  large  in  amount  and  stains  an  intense  red.  In  the 
fully  developed  form,  just  before  the  development  of  the  micro  gametes  or  flagella, 
the  chromatin  is  seen  to  be  divided  into  from  four  to  eight  masses,  which  are 
collected  at  the  periphery  of  the  organism.  In  those  organisms  which  are 
stained  while  undergoing  exflagellation,  the  chromatin  may  be  traced  into  the 
flagella,  and  when  the  process  is  complete  the  body  of  the  micro gametocyte  is 
generally  entirely  free  of  chromatin.  In  such  forms  the  protoplasm  stains  a 
pale  blue,  while  the  pigment,  in  the  form  of  minute  dots  or  very  slender,  short 
rods,  stains  a  greenish- blue  in  color.  The  pigment  is  larger  in  amount  than  in 
the  macrogamete. 

In  the  micro gametocytes  the  chromatin  is  much  larger  in  amount  than  in  the 
macrogametes,  sometimes  comprising  from  one-third  to  one-half  of  the  parasite; 
it  is  often  collected  into  large  irregular  masses  or  in  well-defined  fibrils,  some  of 
which  are  of  considerable  thickness.  According  to  Zieman,  the  proportion  of 
chromatin  to  plasma  in  the  micro  gametocytes  is  from  i  to  i  to  i  to  4,  while  in  the 
macro  gometes  it  is  from  1  to  8  to  1  to  12. 

In  stained  specimens  the  shape  of  the  micro  gametocytes  is  oval  or  circular 
prior  to  the  development  of  the  microgametes ,  and  they  are  smaller  than  the 
macrogametes,  and  are  seldom  larger  than  the  fully  developed  schizont. 

The  following  points  serve  to  differentiate  the  micro  gametocyte  of  Plasmo- 
dium vivax  from  the  macrogametes: 

1.  The  pale  blue  staining  of  the  protoplasm. 

2.  The  larger  amount  of  chromatin  and  its  arrangement  in  masses. 

3.  In  the  fresh  specimen  the  lesser  amount  of  amoeboid  motion. 

4.  In  fresh  specimens  the  greater  amount  of  pigment  which  is  much  more 
motile  and  greenish  in  color.  The  movement  of  the  pigment  which  has  aptly 
been  characterized  as  a  "swarming  motion"  serves  to  distinguish  the  micro- 
gametocyte  from  either  the  fully  developed  schizont,  in  which  the  pigment  is 
motionless,  and  from  the  macrogamete,  in  which  the  pigment  is  either  motionless 
or  very  slightly  motile  and  generally  arranged  in  a  wreath-like  manner. 

5.  The  presence  of  flagella  or  microgametes. 

6.  The  smaller  size  of  this  form  of  the  plasmodium. 

The  Microgametes. — The  micro  gamete  of  Plasmodium  vivax  in  stained 
preparations  of  blood  is  seen  to  consist  of  a  mass  of  pale  blue  stained  protoplasm 
containing  a  considerable  amount  of  brilliant  red  chromatin,  in  the  form  of 
threads,  granules,  or  irregular  masses.  The  shape  of  the  organism  is  thread- 
like with  pointed  ends,  and  it  may  well  be  likened  to  a  spirochaete  devoid  of  an 
undulating  membrane.  Most  of  the  microgametes  consist  very  largely  of 
chromatin,  only  a  small  amount  of  protoplasm  being  visible,  but  occasionally 
the  chromatin  is  small  in  amount  or  even  absent.  Where  no  chromatin  is 
present  it  is  certain  that  the  microgametes  are  sterile.  The  above  description 
applies  to  the  free  microgametes,  the  appearance  of  those  still  attached  to  the 
parent  body  having  already  been  noticed. 

The  Sporogenic  Forms  of  Plasmodium  Malariae  Occurring  in  Human 


48  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

Blood. — The  gametes  of  Plasmodium  malariae,  the  quartan  malarial  Plasmo- 
dium, are  very  similar  to  those  of  Plasmodium  vivax.  in  both  fresh  and  stained 
specimens  of  blood,  and  I  shall  describe  them  but  briefly,  as  much  that  has  been 
said  regarding  the  gametes  of  Plasmodium  vivax  is  equally  true  of  the  gametes  of 
Plasmodium  malari.c. 

The  Gametes. — The  gametes  resemble  very  closely  those  of  Plasmodium 
vivax  in  all  stages  of  intracorpuscular  development,  and  can  only  be  dis- 
tinguished by  their  smaller  size  and  the  absence  of  swelling  of  the  infected 
red  blood-corpuscle.  After  becoming  fully  developed  and  extracorpuscular, 
male  and  female  forms  may  be  distinguished,  the  micro gametocytes  and  the 
macro  gametes. 

The  Macrogametes.— The  macrogametes  of  Plasmodium  malariae  are 
very  hard  to  distinguish  from  the  schizonts,  as  the  quartan  plasmodium  is 
always  round  in  form  and  lacks  amoeboid  motion  after  the  development  of 
pigment.  In  the  earliest  stage  the  absence  of  the  nutritive  vacuole,  or  achromatic 
zone,  in  stained  specimens,  is  distinctive  of  a  gamete,  but  the  quartan  sclvizont 
also  loses  the  achromatic  zone  at  an  early  stage  of  development,  and  the  dis- 
tinction becomes  impossible.  In  the  fully  developed  macro  gamete  the  granular, 
solid  appearing  protoplasm  and  the  greater  amount  of  very  [coarse  pigment 
renders  the  distinction  less  difficult.  In  stained  specimens  the  free  macro- 
gametes are  distinguished  by  their  large  size  (n  to  12  microns  in  diameter)  and 
smaller  amount  of  undivided  chromatin. 

The  Microgametocytes. — The  description  already  given  of  the  micro- 
gametocyte  of  Plasmodium  vivax  is  true,  in  most  respects,  of  the  microgameto- 
cytes of  the  quartan  plasmodium.  There  is  the  same  pale  staining  protoplasm, 
the  large  amount  of  chromatin,  the  swarming  pigment,  and  the  development 
of  microgametes  or  flagella,  which  are  formed  in  the  same  manner,  and  present 
the  same  appearances  in  both  fresh  and  stained  specimens  of  blood.  They 
differ  from  the  tertian  microgametocytes  in  their  smaller  size  and  less  motile 
pigment,  which  is  in  larger  granules. 

The  Microgametes. — The  description  given  of  the  microgametes  of 
Plasmodium  vivax  is  equally  true  for  the  microgametes  of  the  quartan  plasmo- 
dium and,  so  far  as  I  am  aware,  we  have  no  data  sufficient  to  distinguish  this 
form  of  the  two  plasmodia. 

The  Sporogenic   Forms   of   Plasmodium  Falciparum   and    Plasmodium 
Falciparum  Quotidianum  Occurring  in  Human  Blood. 

The  sporogenic  forms,  or  gametes,  of  the  aestivo-autumnal  plasmodia  are 
distinguished  from  similar  forms  of  other  human  malarial  plasmodia  by  their 
crescentic  shape,  a  peculiarity  which  makes  their  differentiation  easy  and 
possible  to  even  the  tyro  in  the  examination  of  malarial  blood.  As  the  differ- 
ences between  the  gametes  of  the  malignant  tertian  and  the  quotidian  aestivo- 
autumnal  plasmodia  are  merely  differences  in  size  and  in  shape,  I  shall  not 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  49 

describe  these  forms  separately,  but  shall  consider  the  general  morphology  of 
the  aestivo-autumnal  gametes  in  both  fresh  and  stained  specimens  of  blood, 
noting  the  differential  points  between  the  two  species  as  suggested  by  the  general 
description. 

The  crescents  occur  only  in  the  blood  of  aestivo-autumnal  infections,  and 
only  after  the  infection  has  persisted  for  some  time.  Canalis  claims  that  he  has 
never  but  once  seen  crescentic  bodies  in  the  peripheral  blood  before  the  fifteenth 
day  of  the  disease,  but,  in  most  instances,  they  may  be  found  in  cases  after 
the  disease  has  been  active  for  something  over  a  week,  twelve  days  being  the 
average  time  for  their  development.  They  persist  in  the  blood  for  weeks  after 
the  active  symptoms  of  infection  have  ceased  and  gradually  disappear  unless 
new  infection  occurs.  They  are  not  affected  by  quinin,  nor  do  we  know  of  any 
drug  that  is  capable  of  destroying  this  form  of  the  plasmodia.  This  is  also 
probably  true  of  the  gametes  of  the  benign  tertian  and  quartan  plasmodia. 

Although  the  crescentic  shaped  gametes  develop  in  a  considerable  proportion 
of  aestivo-autumnal  infections,  it  is  by  no  means  true  that  every  such  infection 
shows  these  forms,  and  from  personal  observation,  both  in  the  tropics  and  in 
this  country,  I  believe  that  not  over  50  per  cent,  of  such  infections  present 
crescents  in  the  peripheral  blood.  If  blood  from  the  spleen  be  examined  or 
smears  of  the  bone-marrow,  crescents  will  be  observed  in  a  greater  proportion 
of  cases,  but  in  many  aestivo-autumnal  infections  the  formations  of  gametes 
appears  to  be  entirely  absent.  Manson  believes  that  crescents  are  more 
frequently  observed  in  cases  of  malaria  which  have  been  contracted  in  the 
tropics,  but  have  returned  to  temperate  regions,  and  that  in  the  tropics  it  is 
much  more  rare  to  observe  this  form  of  plasmodia.  I  do  not  agree  with  this, 
for  I  have  found  that  the  percentage  of  cases  showing  crescents  in  the  tropics 
is  practically  the  same  as  in  temperate  regions.  It  often  requires  a  long  and 
patient  search  to  demonstrate  the  presence  of  crescents  in  the  blood  of  individuals 
who  have  suffered  from  aestivo-autumnal  infections,  and,  while  I  believe  that  a 
prolonged  search  would  show  crescents  in  50  per  cent,  of  such  cases,  still  in  the 
study  of  several  hundred  cases  I  have  only  been  able  to  demonstrate  this 
form  in  a  little  over  33  per  cent.  Rogers  found  that  crescents  were  present 
in  only  10  per  cent,  of  the  cases  he  observed  in  Europe. 

The  crescentic  gametes  of  the  aestivo-autumnal  plasmodia,  like  the 
gametes  of  the  benign  tertian  and  quartan  plasmodia,  develop  within  the  red 
corpuscle,  and,  when  fully  grown,  can  be  differentiated  into  male  and  female 
forms,  the  micro  gametocytes  and  the  macro  gametes.  Their  after-development 
is  similar,  the  micro gametocyte  developing  microgametes  which  become  free 
and  fertilize  the  macrogametes.  The  process  of  microgamete  formation,  or 
flagellation,  as  it  is  called,  may  be  observed  in  blood  which  has  been  removed 
from  the  body  for  some  time  and  in  which  a  sufficient  amount  of  moisture 
is  present,  and  does  not  differ  from  the  same  process  as  observed  in  the  gametes 
of  tertian  and  quartan  plasmodia,  which  has  already  been  described.  The 
crescentic  micro  gametocyte  becomes  oval  and  later  round  in  form,  after  which 
4 


$0  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

the  microga nicies  or  tlagella  are  developed  as  in  the  other  malarial  plasmodia 
(see  Fig.  10). 

Fresh  Preparations. — The  crescentic  gametes  of  the  aestivo-autumnal 
Plasmodia  are  developed  within  the  red  corpuscles  and  during  their  intra- 
corpuscular  stage  are  distinguished  from  the  schizonts  by  their  limited  amoeboid 
motion,  the  early  development  of  a  greater  amount  of  pigment  within  them, 
the  crescentic  or  ovoid  form  acquired  during  the  latter  stages  of  intracorpuscular 
development,  and  their  longer  period  of  development.  Their  protoplasm  is 
more  opaque  and  granular  in  appearance  and  the  pigment  is  darker  in  color. 
Just  before  the  gametes  are  liberated  from  the  red  corpuscles  they  have  become 
definitely  crescentic  in  shape  and  may  be  differentiated  into  male  and  female 
forms.  The  red  cell  has  shrunk  about  the  parasite,  forming  a  membrane- like 
covering,  one  portion  of  which,   that  connecting  the  poles  of  the  crescent, 


Fig.  io. — Tertian  aestivo-autumnal  "ring  form"  and    microgametocyte. 
(Ovoid  form.)     Photomicrograph   X  1200. 

forms  a  hemispherical  projection,  the  so-called  "bib"  of  the  crescent.  In 
the  youngest  crescentic  forms  the  pigment  is  distributed  throughout  the  proto- 
plasm, but  in  the  older  forms  it  becomes  collected  at  the  center  or  toward  one 
of  the  extremities.  The  border  of  the  crescent  is  sharply  defined,  being 
represented  by  a  single  or  double  refractive  outline,  often  of  a  bright  green 
color,  due  to  the  color  of  the  red  corpuscle  which  forms  an  enveloping  mem- 
brane. The  pigment  in  the  crescentic  gametes  is  generally  immotile,  but  in  a 
few  instances  I  have  observed  sluggish  motility. 

The  Macrogamete. — The  macro  gamete,  or  female  crescent,  in  both 
species  of  aestivo-autumnal  plasmodia,  is  distinguished  from  the  microgame- 
tocyte, or  male  crescent,  by  its  slender  form,  the  arrangement  of  pigment,  and  the 
fact  that  it  does  not  develop  microgametes  or  flagella.  This  form  measures 
from  11  to  15  micra  in  length  by  2  to  3  micra  in  breadth.  The  pigment 
is  dark  brown  in  color,  immotile,  and  either  concentrated  in  the  center  of  the 
crescent  in  a  dense  mass  or  arranged  in  a  wreath-like  manner  near  the  center 
of  the  parasite.  The  protoplasm  is  opaque  and  granular  in  appearance.  After 
becoming  extracellular,  which  normally  occurs  within  the  stomach  of  the 
mosquito,  but  which  may  often  be  observed  in  human  blood,  the  macrogamete 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  5 1 

becomes  first  ovoid  and  then  circular  in  shape,  having  a  clear-cut  hyaline  border, 
a  granular  protoplasm,  and  the  pigment  arranged  in  a  wreath-like  manner 
about  the  center  of  the  organism.  Not  infrequently  the  pigment  is  divided 
into  small,  almost  black  dots,  arranged  in  a  perfect  circle  midway  between  the 
center  and  the  periphery  of  the  parasite. 

The  macro  gametes  of  the  quotidian  aestivo-autumnal  plasmodium  are 
distinguished  from  those  of  the  tertian  by  their  smaller  size,  the  pointed 
extremities  of  the  crescent,  the  smaller  amount  of  pigment,  and  its  division 
into  fine  granules  instead  of  into  rods,  the  less  granular  protoplasm,  and  the 
absence,  at  any  time,  of  a  double  outline.  The  quotidian  macro  gamete  never 
measures  more  than  8  or  9  microns  in  length,  while  the  malignant  tertian 
generally  exceeds  12  microns. 

The  Microgametocyte. — The  micro  gametocytes  of  both  species  of 
aestivo-autumnal  plasmodia  are  shorter  and  plumper  in  appearance  than  are 
the  macrogametes,  being  kidney-shaped  rather  than  crescentic.  They  measure 
7  to  10  microns  in  length  by  3  to  5  microns  in  breadth,  and  may  have  a  double 
or  single  border  of  a  greenish  color.  The  protoplasm  is  less  opaque  and 
granular  than  in  the  macrogametes  and  the  pigment  is  in  finer  particles  and 
distributed  throughout  the  protoplasm  or  collected  at  the  poles  of  the  crescent. 
As  in  the  other  malarial  plasmodia,  the  micro  gametocytes,  when  liberated  from 
the  corpuscle  in  which  they  have  developed,  produce  microgametes  or  flagella. 
This  process  is  often  observed  in  properly  collected  specimens  of  human  blood 
and  is  essentially  the  same  as  the  like  process  already  described  in  the  benign 
tertian  and  quartan  plasmodia.  The  crescentic  or  kidney-shaped  microgame- 
tocyte becomes  ovoid  and  then  round,  the  pigment  becomes  very  actively  motile, 
the  entire  protoplasm  of  the  organism  appears  violently  agitated,  and  soon  one 
or  more  slender  filaments  are  projected  from  the  periphery  of  the  organism 
and  lash  about  among  the  surrounding  blood-corpuscles.  These  filaments 
are  the  microgametes.  The  micro  gametocytes  of  the  quotidian  aestivo-autumnal 
plasmodium  are  distinguished  from  those  of  the  malignant  tertian  plasmodium 
by  their  small  size,  seldom  measuring  over  7  microns  in  length,  and  by  their 
very  plump  appearance  which  often  renders  them  ovoid  rather  than  crescentic 
in  shape.     The  pigment  is  also  smaller  in  amount  and  less  motile. 

The  Microgametes. — In  fresh  specimens  of  blood  the  microgametes  of  the 
aestivo-autumnal  plasmodia  appear  as  very  delicate,  hyalin  filaments,  having 
an  active  serpentine  motion,  enabling  them  to  move  about  among  the  blood- 
corpuscles.  The  microgametes  cannot  be  distinguished  from  those  occurring  in 
quartan  and  tertian  infections,  nor  can  the  microgametes  of  the  two  species  of 
aestivo-autumnal  plasmodia  be  distinguished  from  one  another. 

Stained  Preparations. — The  staining  reactions  of  the  aestivo-autumnal 
gametes  are  essentially  similar  to  those  of  the  tertian  and  quartan  gametes, 
when  Wright's  stain  is  used,  the  protoplasm  staining  blue,  the  chromatin  red, 
the  achromatic  zone  surrounding  the  chromatin  in  the  schizont  being  absent 
in  these  forms. 


52  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

The  Gametes. — In  their  earliest  stages  of  development,  the  aestivo- 
autumnal  gametes  are  distinguished  from  the  schizonts  by  their  spherical  shape, 
by  the  deep  blue  staining  of  their  cytoplasm,  by  the  situation  of  the  chromatin 
within  the  center  of  the  parasite  instead  of  at  one  side,  and  by  the  presence 
of  a  deep  red  line  surrounding  the  exterior  of  the  gamete,  in  some  instances. 
In  stained  specimens  the  signet-ring  appearance  so  frequently  observed  in 
aestivo-autumnal  schizonts  is  not  observed  in  the  gametes. 

The  Macrogamete. — In  stained  specimens  the  protoplasm  of  the  macro- 
gamete  is  colored  a  deep  blue,  most  intense  at  the  poles  of  the  crescent;  the 
chromatin  stains  a  brilliant  red  and  is  situated  at  or  near  the  center  of  the 
crescent.  The  pigment  stains  a  greenish-brown  and  often  surrounds  the 
chromatin  as  a  distinct  wreath,  or  is  collected  in  small  circular  masses  near 
the  chromatin.  The  remains  of  the  red  blood-corpuscle  surrounding  the 
crescent  are  stained  a  salmon  or  bright  pink  and  not  infrequently  a  deep  red 
band  may  be  observed  surrounding  macro  gametes  which  are  apparently  free 
in  the  blood  plasma.  The  pink  stained  remains  of  the  red  blood-corpuscle 
often  appear  as. an  irregular,  jagged  rim  around  the  crescent,  and  the  "bib" 
as  a  faintly  staining  mass  occupying  the  concavity  of  the  macrogamete,  having 
a  brightly  stained,  pink  border. 

In  stained  specimens  of  blood  the  aestivo-autumnal  macrogametes  present 
the  following  features  which  enable  us  to  distinguish  them  from  the  micro- 
gametocytes: 

i.  The  long  slender  shape  of  the  crescent. 

2.  The  situation  of  the  chromatin  in  a  dense  mass  at  or  near  the  center  of 
the  crescent. 

3.  The  deep  blue  staining  of  the  protoplasm. 

4.  The  concentration  of  the  pigment  in  little  masses  or  in  a  wreath-like 
manner  about  the  chromatin. 

The  Microgametocyte. — The  protoplasm  of  the  microgametocyte  stains 
a  delicate  blue,  and  in  many  instances  it  is  almost  impossible  to  stain  it  at  all. 
The  chromatin  stains  a  delicate  red  and  is  in  the  form  of  a  loose  network 
spread  over  the  greater  portion  of  the  crescent.  The  pigment  is  granular  in 
appearance  and  is  distributed  throughout  the  crescent.  The  amount  of  stained 
protoplasm  is  very  small  as  compared  with  the  protoplasm  of  the  macrogamete, 
and  the  chromatin  is  often  almost  invisible  on  account  of  the  delicate  fibrils 
of  which  the  chromatin  network  is  composed.  The  staining  of  the  red  blood- 
corpuscle  surrounding  the  microgametocyte  is  similar  to  that  already  described 
for  the  corpuscle  containing  the  macrogamete.  In  stained  specimens  containing 
the  oval  and  round  forms  of  the  microgametocyte,  the  chromatin  is  found  to 
be  collected  in  irregular  masses,  staining  a  deeper  red,  and  situated  toward  the 
periphery  of  the  plasmodium.  The  following  features  enable  us  to  distinguish 
the  aestivo-autumnal  microgametocyte  from  the  macrogamete  in  stained  specimens 
of  blood: 

1.  The  plump  kidney  shape  of  the  crescent. 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 


53 


2.  The  pale  blue  staining  of  the  protoplasm. 

3.  The  pale  red  staining  of  the  chromatin,  which  is  arranged  in  a  loose 
network,  occupying  a  large  portion  of  the  crescent. 

4.  The  distribution  of  the  pigment  throughout  the  protoplasm  of  the 
crescent. 

There  are  no  essential  differences  in  the  staining  reactions  of  the  macro- 
gamete  and  micro gametocytes  of  the  quotidian  and  malignant  tertian  aestivo- 
autumnal  plasmodia. 


Fig.  11. — Aestivo-autumnal  tertian 
macro  gamete.  Note  slender  form. 
Photomicrograph,  X  1200. 


Fig.  12. — Tertian  aestivo-autumnal  micro- 
gametocyte.  Note  plump  form.  Photo- 
micrograph, X  1200. 


The  Microgametes. — As  in  the  quartan  and  benign  tertian  plasmodia, 
the  microgametes  of  the  aestivo-autumnal  plasmodia  are  seen  to  consist,  in 
stained  specimens,  of  a  filamentous  mass  of  chromatin,  enclosed  by  a  small 
amount  of  protoplasm.  No  essential  differences  are  noted  in  the  microgametes 
of  any  of  the  malarial  plasmodia,  so  far  as  staining  reactions  are  concerned. 

Literature  upon  the  Classification  and  Morphology  of  the  Malarial  Plasmodia. 

1885.  Marchiafava   and   Celli.      Weitere   Untersuchungen  uber  die  Malaria- 
infection.     Fortschritte  der  Med.,  No.  24,  p.  787. 

1886.  Osler.      An  Address  on  the  Haematozoa  of  Malaria.     Phil.  Med.  Times. 
1886.     Councilman.     On  Certain  Elements  Found  in  the    Blood   in   Cases  of 

Malarial  Fever.      Trans.  Assoc,  of  Amer.  Phys.,  vol.  i,  p.  90. 

1888.  Celli     and     Guarnieri.      Sulla     struttura     intima     della     plasmodium 
malarise.     Rif.  med.,  7  Sett,  12  Ott. 

1889.  Golgi.      Sullo  sviluppo  de'  parassiti  malarici  nella  febbre  terzana.      Arch, 
per  le  sc.  med.,  vol.  xiii,  p.  173. 

1889.  Canalis.      Studi  sull'  infezione  malarica,  Giornale  medico  del  esercito  e 
della  marina,  Dec,  p.  1329. 

1890.  Grassi   and  Feletti.     Ueber  die  Parasiten  der  Malaria.     Centralbl.  f. 
Bakt.,  vii,  p.  396,  430. 

1890.      Antolisei.      L'ematozoo    della    quartana.      Riforma    Medica,    Nos.     12 
and  13,  p.  68. 


54  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

1S90.      Idem.      Sull'  ematozoo  della  terzana.  Rif.  Med.,  Nos.  26  and  27,  pp.  1  52, 

158. 
1890.     Antolisei    and    Angelini.      Nota    sul    ciclo    biologico    dell'    ematozoa 

falciforme.      Rif.  Med.,  Nos.  54,  55,  56;  pp.  320,  326,  332, 
i8qo.      Axtot.isei.      Considerazioni    intorno    alia    classificazione    del    parasitti 

dell  malaria.      Rif.  Med.,  Nos.  99,  100,  101,  102,  103;  pp.  590,  596,  602, 

60S;  614. 
1890.      Bastianelli  and  Bignami.      Sull'  infezione  malarica  primavirile.      Rif. 

Mod.,  Nos.  144-146,  pp.  860,  866,  872. 
1890.      Kruse.      Ueber  Blutparasiten.      Virch.  Archiv.  Bd.  120,  p.  541;  Bd.  121, 

P-  3  59- 
1S90.      Bastianelli  and  Bignami.      Observazioni  sulle  febbri  malariche  aest i ve- 
autunnali.      Rif.  Med.,  Nos.  223,  2241pp.  J334>  J34°- 

1890.  Romaxowskv.      Sur  la  structure  des  parasites  du  paludisme.     Vratsch, 
No.  52,  Russian. 

1891.  Celli  and  Sanfelice.      Ueber  die  Parasiten  des  roten  Blutkorperchens 
in  Menschen  und  in  Tieren.      Fortschr.  der  Med.,  No.  13,  July  1. 

1891.      Dock.      Die     Blutparasiten     der     tropischen     Malariafieber.     Fortschr. 

der  Med.,  ix,  p.  187. 
1 89 1.      Mannaberg.      Beitrage  zur  Morphologie  und   Biologie  des  Plasmodium 

Malarias  Terzianae.      Centralbl.  fur  klin.  Med.,  No.  27. 

1891.  Marchiafava  and    Bignami.      La  quotidiana  e  terzana  estivo-autunnali. 
Rif.  Med.,  No.  217,  p.  703. 

1892.  Dock.      The  Parasite   of  Quartan   Malarial  Fever.      International   Med. 
Magazine,  1,  p.  28. 

1892.     Marchiafava    and    Bignami.     Aestivo-autumnal    Malaria.     The    New 

Sydenham  Society,  vol.  cl,  London,  1894. 
1802.      Kruse.      Der   gegenwartige    Stand    unserer    Kenntniss    der   parasitaren 

Protozoen.      Hygien.  Rundschau,  ii,  Nos.  9,  11,  pp.  357,  453. 
C892.      Ruge.      Ueber   die   Plasmodien   bei    Malaria    Erkrankungen.      Deutsch. 

militarartzliche  Zeitschr.,  xxi,  p.  49. 

1892.  Marchiafava  and  Bignami.     Ueber  die  Varietaten  der  Malariaparasiten. 
Deutsch  med.  Wochenschr.,  Nos.  51,  525  pp.  1157,  1188. 

1893.  Mannaberg.      Die  Malaria  Parasiten.      Wien. 

1893.      Laveran.      Au  sujet  de  l'hematozoaire  du  paludisme.      Compt.  rend.  soc. 

de  biol.     Par.  March  24,  No.  11,  p.  312. 
1893.      Sacharoff.      Zur   Biologie   der  Malariaparasiten.      Ref.    in  Centralbl.  f. 

Bakt.,  xv,  No.  24,  p.  962. 
1893.      Labbe.      A  propos  des  formes  a.  flagella  des  hematozoaires   malariques. 

Compt.  rend.  soc.  de  biol.,  Dec.  9,  p.  980. 
1893.      Bignami   and   Bastianelli.      Stidi  sulla  infezione  malarica.      Bull.    R. 

Accad.      Med.  Roma.,  Anno  xx. 
1S94.      Labbe.      Recherches  zoologiques  et  biologiques  sur  les  parasites  endo- 

globularides  du  sang  des  vertebres.      Arch,  de  zoologie  experim.  et  gen., 

ser.  iii,   t.  ii,  pp.  55-258. 
1896.      Sacharoff.      Ueber  den  Entstehungsmodus  der  verschiedenen  varietaten 

der  Malariaparasiten.      Centralbl.  f.  Bakt.,  xix,  No.  8,  p.  268. 

1896.  Zieman.      Ueber   Blutparasiten  bei   heimischen  und  tropischer   Malaria. 
Central,  f.  Bakt.,  xx,  No.  18  and  19. 

1897.  Sternberg.,  G.   M.      The  Malarial  Parasite  and  other   Pathogenic   Pro- 
tozoa. Am.  Medico-Surgical  Bull.,  xi,  No.  7,  p.  328. 

1897.      Zieman.      Zur   Morphologie  der  Malariaparasiten.      Centralbl.   f.    Bakt., 
xxi,  No.   17,  18,  20,  21. 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  55 

1897.  McCallum.  On  the  Flagellated  Form  of  the  Malarial  Parasite.  Lancet, 
No.  13,  p.  1240. 

1898.  Zieman.  Neue  Untersuchungen  liber  die  Malaria,  etc.  Deutsche  med. 
Wochenschr.,  No.  8,  p.  123. 

1898.      Gautier.      Malariastudien.  Zeitschr.  f.  Hyg.  u.  Infekt.,  Bd.  xxviii,  p.  439. 

1898.  Ewing,  James.  Comparative  Morphology  of  Malarial  Plasmodia.  Med. 
News,  lxxiii,  No.  25,  p.  728. 

1899.  Bignami  and  Bastianelli.  Sulla  struttura  dei  parassiti  malarici. 
Ann.  dig.  sperimentali,  Anno  xx. 

1899.      Laveran.      Les  Hematozoaires  endoglobulaires.      (Haemocytozoa).  Cin- 

quantenaire  de  I.  soc.  d  Biol.  Paris,  Oct.  27,  p.  124. 
1899.      Schuffner.      Beitrag.  zur  Kenntnis  der  Malaria.      Deutsch.  Arch.  f.  klin. 

Med.,  lxiv,  p.  428. 

1899.  Craig,  C.  F.  Observations  upon  Flagellated  Malarial  Plasmodia.  New 
York  Med.  Jour.,  Dec.  23,  1899. 

1900.  Luhe.      Ergebnisse  der  neueren  Sporozoenforschung.  Jena. 

1900.  Craig,  C.  F.  The  Parasites  of  Aestivo-autumnal  (Remittent)  Malarial 
Fever.     Phil.  Med.  Jour.,  April  7. 

1900.  Idem.  Observations  upon  the  Quartan  Malarial  Parasite  and  upon  the 
Staining  Reactions  of  the  Tertian,  Quartan  and  Aestivo-autumnal 
Parasites.      Med.  News,  November  3,  1900. 

1901.  Argutinsky.      Malariastudien.    Arch.  f.  mikroskop.  Anat.,Bd.  lix,  p.  3  1  5. 
1901.      Grassi.      Die  Malaria.      Studien  eines  Zoologen.     Jena. 

1901.      Maurer.      Die  Malariaparasiten.      Munch,  med.  Wochenschr.,  xlix,  No.  9, 

P-  337- 

1901.     Ewing,  James.     Parasitology.     Jour.  Exper.  Med.,  No.  5,  p.  429. 

iyoi.  Lazear.  Structure  of  the  Malarial  Parasites.  Johns  Hopkins  Hosp. 
Rep.,  vol.  x,  p.  1. 

1 90 1.  Schuffner.  Zur  Tiipfelung  der  roten  Blutscheiben  bei  Febris  inter- 
mittens tertiana.      Deutsch.  Archiv.  f.  klin.  Med.,  lxxi,  No.  4  and  5. 

1901.  Craig,  C.  F.  The  Aestivo-autumnal  (Remittent)  Malarial  Fevers.  New 
York. 

1902.  Arguntinsky.  Malariastudien.  Zur  Morphologie  des  Tertiansparasiten. 
Arch.  f.  mikroskop.  Anat.,  Bd.  lxi,  p.  331. 

1902.  Schaudinn.  Studien  uber  krankheitserregende  Protozoen.  II.  Plas- 
modium vivax;  etc.  Arb.  a.d.  Kaiserl.  Gesundheitsamte,  Bd.  xix,  No.  2, 
p.  169. 

1902.  Maurer.  Die  Malaria  perniciosa.  Centralbl.  f.  Bakt.,  Bd.  xxxii,  No. 
10,  p.  695. 

1902.  Ruge.  Fragen  und  Probleme  der  moderner  Malaria-forschung.  Centralbl. 
f.  Bakt.,  Bd.  xxxii,  No.  n,  p.  776. 

1903.  Argutinsky.  Zur  Kenntnis  des  Tropicaparasiten.  Centralbl.  f.  Bakt., 
Bd.  xxxiv,  p.  144. 

1904.  Rowley.  Some  Unusual  Forms  of  Malarial  Parasites.  Johns  Hopkins 
Hosp.  Bull.,  vol.  xv,  No.  154,  p.  1. 

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Leipzig. 

1907.  Manson.      Tropical  Diseases.      New  York. 

1907.  Thayer.  Malaria.  System  of  Medicine.  Allbut  and  Rolleston.  Lon- 
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1907.  Craig,  C.  F.  The  Malarial  Fevers.  Modern  Medicine.  Osier.  Phila- 
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Journ.,  May  27,  vol.  clx,  No.  21,  p.  677. 


GOLLEG:  tORS 

COLL  S\IY 


CHAPTER  III. 

Development  of  the  Malarial  Plasmodia  Within  the  Mosquito:  Mosquitoes; 
Structure;  Ova;  Larvae;  Pupae;  Habits;  Distribution;  Classification.  Mosquitoes 
Proven  to  Transmit  Malaria;  The  Relation  of  Number  of  Infected  Mosquitoes 
to  Malarial  Infection  in  Various  Localities. 

Development  of  the  Malarial  Plasmodia  within  the  Mosquito. — In  the 
previous  chapter  I  have  described  the  forms  of  the  malarial  plasmodia  destined 
to  undergo  development  within  the  mosquito  and  which  may  be  observed  in  the 
blood  of  man.  Thus  I  have  described  the  macro  gametes,  the  micro  gametocytes 
and  the  micro  gametes,  and  also  the  fertilization  of  the  macrogamete  by  the 
micro  gamete,  a  process  which  may  be  observed  in  human  blood  after  it  has  been 
removed  from  the  body,  but  which  normally  occurs  in  the  middle  intestine  of 
the  mosquito.  In  this  chapter  I  shall  describe  the  changes  occurring  after  the 
fertilization  of  the  macrogamete  and  trace  the  cycle  of  development  of  the 
plasmodia  within  the  mosquito. 

Historical  Summary. — The  conception  that  mosquitoes  transmit  malaria 
is  by  no  means  a  recent  one,  such  a  theory  having  been  held  by  the  early  Roman 
observers,  Varro,  Columella,  and  Vitruvius.  Many  of  the  people  of  both  civilized 
and  uncivilized  nations  have  believed  that  these  fevers  are  due  to  the  mosquito, 
and  Koch  is  authority  for  the  statement  that  in  German  East  Africa  the  native 
name  for  malaria,  Mbu,  is  also  the  native  name  for  the  mosquito,  and  that  the  peo- 
ple firmly  believe  that  the  fever  is  due  to  the  bite  of  these  insects.  In  1848, 
Nott,  of  New  Orleans,  in  a  paper  upon  yellow  fever,  speaks  of  the  transmission  of 
malaria  by  the  mosquito  as  a  fact,  and  in  1883,  King,  of  Washington,  advocated 
this  theory  very  vigorously,  and  compiled  a  great  mass  of  evidence  in  its  favor. 
After  the  appearance  of  King's  paper,  numerous  writers  published  arguments 
in  favor  of  such  a  method  of  transmission,  chief  among  whom  may  be  mentioned 
Laveran,  in  1884 ;  Flugge,  in  1891 ;  Pfeiffer,  in  1892,  and  Manson,  in  1 894 . 

In  1896,  in  his  Goulstonian  lectures,  Manson  anew  directed  attention  to 
this  subject,  and  while  some  of  his  deductions  have  been  proven  to  be  erroneous, 
it  is  unquestionably  true  that  to  this  author  we  owe  the  stimulation  of  interest 
which  resulted  in  the  discovery  of  the  true  relation  of  the  mosquito  to  the 
malarial  fevers.  Manson  stated  in  these  lectures  his  belief  that  the  crescentic 
and  flagellated  parasites  are  the  extracorporeal  sporulating  homologues  of  the 
intracorporeal  sporulating  plasmodia,  and  that,  as  the  mosquito  had  been  proven 
to  remove  from  man  Filaria  noctuma,  acting  afterward  as  a  host  of  this  parasite, 
so  the  same  insect  might  remove  these  extracorporeal  bodies  of  the  malarial 
parasites  and  constitute  the  host  for  these  particular  bodies.  Manson  did  not, 
at  that  time,  believe  that  the  mosquito  inoculated  malaria  into  man,  but  that 
the  insect  removed  from  man  certain  stages  of  the  plasmodium  which  afterward 
underwent  development  within  the  mosquito,  and  which  were  then  liberated 
in  the  water  and  dust  and  thus  infected  man. 

56 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  57 

To  Ross,  a  Surgeon-Major  of  the  Indian  Army  Medical  Service,  we  owe  the 
discovery  of  the  true  relation  of  the  mosquito  to  the  malarial  fevers.  Stimulated 
by  Manson's  theories  regarding  this  subject,  this  investigator,  in  1895,  studied 
the  development  of  the  parasites  of  aestivo-autumnal  fever  in  the  mosquito,  and 
proved  that  the  crescents  underwent  definite  changes  within  the  stomach  of 
the  insect,  flagella  developing  in  the  same  manner  as  has  been  described  when 
this  process  occurs  in  the  blood  of  man.  Later  this  investigator,  in  1897, 
described  the  large  cyst-like  bodies  situated  in  the  outer  layer  of  the  stomach 
wall,  and  considered  that  these  were  developmental  forms  of  the  plasmodia 
within  the  tissues  of  the  mosquito,  and  that  he  had  at  last  been  successful  in 
finding  the  mosquito  in  which  the  malarial  plasmodia  underwent  their  extra- 
corporeal cycle  of  development. 

In  1896  Bignami  stated  it  as  his  belief  that  the  mosquito  inoculated 
malaria  in  man  during  the  act  of  biting,  the  organisms  being  introduced  with 
the  saliva  of  the  insect,  and  that  this  method  of  transmission  of  the  disease  is  of 
greater  importance  than  transmission  by  air  or  water. 

In  1898  Ross  studied  very  carefully  the  malaria  of  birds,  due  to  proteosoma 
and  halteridium.  In  mosquitoes  which  had  been  allowed  to  bite  birds  infected 
with  proteosoma,  he  found  in  the  stomach  wall  large  pigmented  bodies  similar 
to  those  observed  previously  in  mosquitoes  which  had  bitten  malarial  subjects; 
he  found  that  these  bodies  increased  in  size  until  they  protruded  from  the 
stomach  wall  of  the  insect,  and  that  there  developed  within  them  a  large  number 
of  delicate  thread-like  bodies,  which,  after  rupture  of  the  cyst  in  which  they 
had  developed,  were  liberated  into  the  body-cavity  of  the  insect.  He  was  able 
to  trace  these  bodies  to  the  cells  and  ducts  of  a  gland  located  in  the  thorax,  and 
which  possesses  an  efferent  duct  leading  into  the  proboscis.  This  gland  Ross 
considered  as  a  venemo-salivary  gland,  and  he  then  advanced  the  theory  that 
the  thread-like  bodies  were  injected  into  the  bird  when  the  insect  bit,  and  that 
they  began  anew  the  life  cycle  of  the  proteosoma  in  the  bird.  He  proved  this 
theory  experimentally  by  allowing  infected  mosquitoes  to  feed  on  healthy  birds, 
and  found  that  "1.  Out  of  28  originally  healthy  sparrows  subjected  to  the 
bites  of  gray  mosquitoes  previously  fed  on  diseased  sparrows,  22,  or  79  per  cent., 
became  infected,  all  with  a  very  large  number  of  parasites,  in  from  five  to  eight 
days.  2.  Out  of  two  crows  and  four  weaver-birds,  one  of  the  crows  and  all  of 
the  weaver-birds  showed  a  copious  proteosoma  infection  within  nine  or  ten  days 
of  being  bitten  by  gray  mosquitoes  fed  previously  on  sparrows  with  proteosoma." 
Ross  was  thus  able  to  prove  beyond  question  that  the  malaria  of  birds  is  trans- 
mitted by  the  mosquito,  and  he  stated  it  as  his  belief  that  what  had  been  found 
true  of  bird  malaria  would  also  be  found  true  of  human  malaria. 

In  1897  MacCallum,  in  studying  the  development  of  halteridium,  a  blood 
parasite  of  birds,  observed  that  the  fully  developed  extracellular  halteridium 
consisted  of  two  forms,  one  of  which  was  flagellated,  the  other  non-flagellated. 
He  observed  that  the  flagella,  breaking  away  from  the  flagellated  form,  pene- 
trated the  ncn-flagellated  organisms,  and  that  after  penetration  a  motile  body  re- 
sulted which  moved  about  among  the  blood-corpuscles,  and  which  was  capable  of 
penetrating  and  destroying  them.  His  observation  was  confirmed  later  by  Ross, 
Koch,  and  Marchoux.  The  discovery  of  MacCallum  explained  the  occurrence 
of  pigment  within  the  cystic  bodies  in  the  stomach  of  the  mosquito  and  also 
demonstrated  that  the  development  of  these  organisms  is  sexual  in  nature,  and 
that  the  flagella  alone  are  incapable  of  development. 

The  demonstration,  experimentally,  that  mosquitoes  transmit  malaria  to 
man  we  owe  to  Italian  investigators  who,  following  the  work  of  Ross  and  Mac- 
Callum, endeavored  to  produce  malaria  in  man  by  allowing  infected  mosquitoes 


58  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

to  bite  healthy  individuals.  In  1S98,  in  Rome,  Bignami  endeavored  bo  produce 
malaria  in  man  in  this  way,  but  was  not  successful,  probably  because  he  did  not 
use  the  right  species  of  mosquito  in  his  experiments.  Later  in  the  same  year  this 
observer  was  successful  in  producing  an  attack  of  aestivo-autumnal  malaria  in 
man  by  allowing  mosquitoes  which  had  bitten  an  infected  individual  to  bite  a 
patient  who  had  never  had  malaria.  In  the  same  year,  Bastianclli,  Bignami, 
and  Grassi  were  successful  in  producing  a  double  tertian  infection  in  man  by 
the  bites  of  infected  Anopheles.  In  February,  1899,  they  were  successful  in 
infecting  Anopheles  maeitli pcmiis  with  quartan  plasmodia,  and  were  able  to 
trace  the  developmental  stages  of  this  species  of  Plasmodium  in  the  mosquito. 
They  were  also  able  to  report  a  second  successful  experiment  with  the  benign 
tertian  Plasmodium  and  another  with  the  aestivo-autumnal  Plasmodium.  In 
April,  1S99,  Bastianelli  and  Bignami  reported  three  successful  inoculation 
experiments,  the  first,  a  double  tertian  infection;  the  second,  a  tertian  infection, 
and  the  third,  an  infection  with  one  of  the  aestivo-autumnal  plasmodia.  The 
experiments  of  the  Italian  observers  have  been  again  and  again  confirmed  by 
numerous  investigators  whose  results  will  be  considered  fully  in  the  chapter  of 
this  work  dealing  with  the  methods  of  transmission  of  the  malarial  fevers. 

General  Description  of  the  Mosquito  Cycle  (Sporogony). — I  have 
already  described  the  process  of  flagellation,  as  it  is  called,  and  the  fertilization 
of  the  macro  gamete,  or  female  plasmodium,  by  the  microgamete,  or  male  Plasmo- 
dium. This  process  occurs  in  nature  in  the  middle  intestine  of  the  mosquito, 
after  the  insect  has  bitten  an  infected  individual.  The  result  of  this  fertilization 
is  known  as  the  zygote  or  sporont.  After  a  certain  period  of  time  the  zygote 
becomes  elongated  and  finally  motile  and  is  then  known  as  the  ookinete.  The 
ookinete  penetrates  the  wall  of  the  middle  intestine  and  eventually  becomes 
situated  on  the  outer  side  of  the  epithelium  and  the  basement  membrane  of  the 
intestine  between  the  adipose  tissue  and  the  muscular  wall.  Here  the  organism 
becomes  spherical  in  shape  and  forms  a  cyst  known  as  the  oocyst.  At  this 
stage  the  protoplasm  is  granular  and  reticular  in  appearance,  the  pigment  is 
reduced  in  amount,  and  the  entire  organism  is  enclosed  within  a  well-defined 
capsule.  The  oocyst  is  formed  at  about  the  third  or  fourth  day  after  infection 
of  the  mosquito.  About  the  fifth  or  sixth  day  the  oocyst  enlarges  and  within  it 
are  formed  spherical  refractive  bodies  known  as  sporoblasts.  At  this  stage  the 
organism  is  increased  so  much  in  size  that  it  projects  from  the  intestinal  wall. 
Besides  the  sporoblasts,  the  cyst  contains  some  pigment  and  minute  granules 
which  resemble  fat.  At  the  end  of  a  week  the  sporoblasts  have  produced  a  large 
number  of  delicate  filaments  having  pointed  extremities  and  containing  a  small 
amount  of  nuclear  chromatin.  These  filaments  are  the  sporozoites,  measure 
about  14  microns  in  length,  and  are  arranged  in  a  ray-like  manner  about  a 
central  mass  which  may  contain  pigment.  At  this  stage  the  capsule  of  the 
oocyst  is  very  distinct.  The  sporozoites  are  finally  liberated  by  the  rupture  of  the 
oocyst  and  gradually  make  their  way  to  the  cells  and  tubules  of  the  salivary 
glands  of  the  insect.  When  this  has  occurred  the  mosquito,  in  the  act  of  biting, 
will  inoculate  the  sporozoites,  which,  penetrating  the  red  blood-cells,  develop 
into  merozoitcs,  and  the  human  cycle  of  the  plasmodium  begins.     The  entire 


THE    ETIOLOGY    OF    THE    MALARIAL    LEVERS.  59 

cycle  of  development  in  the  mosquito  is  completed  in  from  10  to  14  days,  so  that 
the  insect  may  bite  two  or  three  times  before  it  is  infectious. 

The  following  biological  terms  are  applied  to  the  forms  of  the  malarial 
plasmodia  concerned  in  sporogony,  or  development  within  the  mosquito. 

1.  Macrogamete,  in  tertian  and  quartan  infections  the  female  spherical 
bodies,  and  in  aestivo-autumnal  infections  the  female  crescent. 

2.  Micro gametocyte,  in  tertian  and  quartan  infections  the  male  spherical 
bodies,  and  in  aestivo-autumnal  infections  the  male  crescent. 

3.  Microgamete,  the  liberated  flagellum  of  the  micro  gametocyte. 

4.  Zygote  or  sporont,  the  result  of  the  fertilization  of  the  macrogamete  by 
the  microgamete. 

5.  Ookinete,  the  motile  stage  of  the  zygote  or  sporont. 

6.  Oocyst,  the  cystic  stage  of  the  ookinete. 

7.  SporoUasls,  developed  within  the  oocyst. 

8.  Sporozoites,  bodies  developed  within  the  sporoblasts  and  liberated  by  the 
rupture  of  the  oocyst,  which  are  introduced  into  man  by  the  mosquito,  and 
which  are  capable  of  beginning  the  human  life  cycle,  or  schizogony,  of  the 
plasmodia  by  infecting  the  red  blood-corpuscles. 

The  cycle  of  development  within  the  mosquito  has  been  studied  in  all 
species  of  malarial  plasmodia,  and  infection  of  man  by  the  mosquito  has  been 
demonstrated  with  all  species  of  the  plasmodia. 

Detailed  Description  of  Sporogony  of  the  Plasmodia  of  Malaria. — A 
great  amount  of  study  has  been  devoted  to  the  changes  occurring  in  the  plasmo- 
dia of  malaria  during  sporogony,  and  it  may  be  stated  that  every  stage  of  this  life 
cycle  has  been  thoroughly  investigated  and  described  by  numerous  writers 
upon  the  malarial  fevers.  The  following  description  is  derived  partly  from 
personal  observations  and  partly  from  the  observations  of  others,  notably  those 
of  Schaudinn,  Grassi,  Bastianelli,  and  Bignami. 

Previous  to  the  formation  of  the  microgametes,  the  micro gametocytes  undergo 
certain  changes  which  are  of  interest.  The  nucleus  gives  off  a  large  amount  of 
chromatin,  which  becomes  arranged  about  the  periphery  of  the  organism,  and 
which  enters  into  the  formation  of  the  thread-like  microgametes.  It  would 
appear  that  this  chromatin  is  taken  up  by  the  microgametes  just  before  the  latter 
emerge  from  the  body  of  the  micro  gametocyte,  for  in  stained  specimens  it  is 
but  seldom  that  any  chromatin  is  observed  in  the  residual  body  immediately 
after  the  appearance  of  the  microgametes. 

The  only  change  observed  in  the  mac  ogamete  prior  to  fertilization  con- 
cerns the  nucleus,  a  portion  of  the  substance  of  which  is  claimed  by  Schaudinn 
to  be  eliminated. 

When  fertilization  occurs,  the  microgamete  penetrating  the  macrogamete, 
the  chromatin  of  the  former  constitutes  a  pronucleus  which  fuses  with  the 
female  pronucleus  of  the  macrogamete,  and  a  fertilization  spindle  is  thus  formed, 
which  is  often  very  well  defined  in  properly  prepared  specimens.  The  organism 
resulting  from  the  union  of  the  micro-  and  macrogamete,  or  the  zygote,  does  not 


6o  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

encyst,  but  develops  into  an  elongated  vermicule  or  ookinete.  This  body  is 
somewhat  oval  in  shape,  the  anterior  extremity  bei.ig  very  narrow  and  pointed 
while  the  posterior  extremity  is  broad  and  rounded  in  appearance.  The 
nucleus  is  situated  a  little  posterior  to  the  middle  of  the  body  and  is  composed 
very  largely  of  chromatin,  which  takes  a  deep  red  stain  with  Wright's  method  of 
staining.  The  pigment  is  collected  in  a  loosely  arranged  mass  near  the  posterior 
extremity  and  later  in  the  development  of  the  ookinete  may  be  extruded  or  may 
be  retained  until  the  formation  of  the  sporozoites,  when  it  is  liberated  together 
with  a  portion  of  residual  protoplasm.  The  movements  of  the  ookinete  are 
very  active,  consisting  of  contractions  of  the  body  and  of  a  rapid  progressive 
motion,  gliding  in  character,  no  satisfactory  explanation  of  which  has  as  yet 
been  given.  Schewiakoff  believes  that  the  gliding  progressive  motion  is  due  to 
the  secretion  and  extrusion  of  a  gelatinous  thread  which  pushes  the  organism 
forward  as  it  is  formed,  while  Crawley  thinks  that  the  motion  is  due  to  wave- 
like contractions  of  the  protoplasm.  However  the  motion  is  produced,  it 
enables  the  ookinete  to  force  its  way  through  the  epithelial  lining  of  the  mos- 
quito's stomach  and  reach  that  portion  of  the  stomach  wall  immediately 
beneath  the  epithelial  lining  where  it  rests  and  the  oocyst  is  formed.  When  it 
reaches  this  locality  the  ookinete  becomes  spherical  in  shape  and  secretes  a 
delicate  covering  membrane,  continuing  to  grow  until  it  projects  from  the 
stomach  wall  toward  the  body  cavity  of  the  insect. 

The  nucleus  divides  and  each  daughter  nucleus  is  surrounded  by  a  portion 
of  protoplasm,  forming  the  sporoblasts;  the  sporozoites  are  developed  within 
the  sporoblasts  by  the  repeated  division  of  the  nucleus  of  each  sporoblast,  the 
small  nuclei  thus  produced  accumulating  upon  the  surface  of  the  sporoblast  and 
forming  delicate  protoplasmic  prolongations,  each  consisting  of  a  little  proto- 
plasm and  a  clump  of  chromatin,  eventually  forming  the  sporozoites.  When 
development  is  complete,  the  cyst  is  filled  with  a  multitude  of  sporozoites  together 
with  some  residual  protoplasm,  and  in  many  instances  considerable  pigment. 
When  the  cyst  ruptures,  the  sporozoites  are  liberated  in  the  body  cavity  of  the 
insect  and  are  carried  by  the  blood  to  the  salivary  glands,  from  which  they  pass 
down  the  proboscis  to  the  blood  of  man  when  the  mosquito  bites.  The 
sporozoites  are  actively  motile,  spindle-shaped,  and  measure  about  14  microns 
in  length. 

The  time  consumed  in  sporogony  has  been  variously  estimated  at  from 
10  to  14  days,  the  average  being  10  to  12  days.  It  varies,  in  all  probability, 
with  each  species  of  plasmodium,  but  never  exceeds  14  days. 

The  fertilization  of  the  macrogamete  by  the  micro  gamete,  first  observed  in 
human  malaria  by  MacCallum,  has  been  observed  by  Koch,  in  Africa,  and  by 
Ashburn  and  myself,  in  the  Philippine  Islands,  in  blood  from  malarial  cases 
removed  for  some  time  from  the  body. 

To  those  who  are  interested  in  tracing  the  development  of  the  malarial 
plasmodia  within  the  mosquito,  the  following  description,  arranged  in  periods 
of  time  may  prove  useful. 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 


6l 


First  and  Second  Days  After  Ingestion  of  Malarial  Blood. — The 
fusiform  and  spindle-shaped  ookinetes  penetrate  the  epithelial  lining  of  the 
insect's  stomach  and  reach  the  muscular  layer,  where  they  encyst  and  form  the 
oocyst.  In  stained  specimens  the  ookinete  presents  at  or  near  the  center  a  deep 
red  chromatin  mass,  representing  the  nucleus,  the  chromatin  being  in  the  form 
of  short,  very  delicate  threads  or  granules.  The  pigment  is  collected  in  a  dense 
clump  at  the  posterior  end  or  is  distributed  throughout  the  protoplasm;  the 


Fig:  13. — Development  of  Plasmodium  vivax  within  the  Mosquito. 
1,  Ookinete;  2,  Oocyst;  3,  4,  5,  Oocysts  showing  the  development  of  sporoblasts;  6  and  7, 
Oocyst  showing  development  of  the  sporozoites,  which  are  fully  formed  in  7;  8,  Sporozoites 
within  a  cell  of  the  salivary  gland;  9,  Sporozoites;  10,  Entrance  of  sporozoite  into  a  red  blood- 
corpuscle;  11,  Middle  intestine  (stomach)  of  mosquito,  showing  several  oocysts  in  the  wall  of 
the  organ. 


protoplasm  contains  numerous  vacuoles  and  stains  a  light  blue  color.  The 
oocyst  at  the  end  of  two  days  is  about  the  size  of  a  red  blood-corpuscle,  con- 
tains considerable  pigment  distributed  throughout  the  protoplasm,  and  the 
chromatin  is  found  in  small  granules  or  in  minute  irregular  masses,  collected 
toward  the  center  of  the  organism. 

Third  and  Fourth  Days. — During  the  third  and  fourth  days  the  oocyst 
increases  to  twice  its  original  size,  and  develops  a  well-marked  cyst  wall.  The 
pigment  is  not  increased  in  amount,  and  is  collected  in  small  masses;  the  proto- 
plasm is  vacuolated  and  the  chromatin  is  distributed  throughout  it  in  fine 
granules  or  delicate  threads. 


62  THE    ETIOLOGY    OF    THE    MALARIAL    LEVERS. 

Fifth  and  Sixth  Days. — At  the  end  of  the  sixth  day  the  cyst  has  in- 
creased very  greatly  in  size,  measuring  from  35  to  75  microns  in  diameter,  and 
projects  from  the  wall  of  the  stomach  outward  toward  the  body  cavity  of  the 
insect.  The  protoplasm  appears  granular,  and  large,  very  refractive  spherical 
bodies  may  be  distinguished  within  it,  the  sporoblasts.  The  pigment  has  not 
increased  in  amount  and,  owing  to  the  great  increase  in  size  of  the  organism, 
appears  to  have  greatly  diminished;  in  some  instances  the  cyst,  at  this  stage,  is 
devoid  of  pigment.  The  chromatin  is  collected  in  the  sporoblasts  and  stains 
red,  while  the  protoplasm  stains  a  very  pale  blue. 

Seventh  to  Eighth  Days. — Under  favorable  circumstances,  and  in  some 
species  of  Anophelina,  the  cysts  have  attained  their  full  growth  in  eight  days. 
At  this  time  a  well-marked  double  outlined  membrane  surrounds  them,  which 
is  perfectly  smooth  in  contour;  the  sporoblasts  form  common  centers  from  which 
radiate  multitudes  of  delicate,  elongated,  spindle-shaped,  or  thread-like  bodies, 
the  sporozoites.  The  sporozoites  appear  to  originate  from  the  outer  layers  of  the 
sporoblasts,  each  sporozoite  being  attached  by  its  inner  extremity  to  a  small 
portion  of  the  residual  protoplasm  of  the  sporoblast.  When  isolated  and 
stained  each  sporozoite  measures  from  12  to  14  microns  in  length,  and  contains 
one  or  more  masses  of  chromatin  imbedded  in  the  light  blue  protoplasm.  When 
fully  developed  the  sporozoites  become  detached  from  the  sporoblasts  and  the 
cyst  is  then  observed  to  be  filled  with  multitudes  of  these  delicate  filamentous 
organisms. 

The  above  description  applies  to  the  tertian  aestivo-autumnal  plasmodium, 
but  practically  the  same  appearances  are  observed  in  the  mosquito  cycle  of  the 
benign  tertian  and  quartan  plasmodia.  It  should  be  remembered  that  in  any 
one  insect  all  of  the  plasmodia  are  not  in  the  same  stage  of  development  at  the 
same  time,  some  being  more  advanced  than  others,  but  the  periods  as  given  are 
true  for  the  vast  majority  of  aestivo-autumnal  plasmodia,  in  most  species  of 
Anophelina.  Unless  the  temperature  be  suitable,  the  development  may  be 
delayed  to  12  or  even  14  days,  and  in  Myzomyia  funesta,  a  very  common  malaria 
carrier,  the  cycle  of  development  at  8o°  F.  always  takes  12  days. 

After  the  sporozoites  are  liberated  into  the  body  cavity  of  the  insect  by  the 
rupture  of  the  cyst  wall  they  may  be  observed  in  fluid  from  any  portion  of  the 
body  of  the  insect,  and  if  the  cells  of  the  salivary  glands  be  examined  numerous 
sporozoites  will  be  seen  within  them,  as  well  as  within  the  salivary  ducts. 

Mosquitoes. 

A  good  working  knowledge  of  the  structure,  habits,  distribution,  and 
classification  of  mosquitoes  is  essential  to  the  student  of  malaria  and  to  the 
practitioner  of  medicine,  especially  in  tropical  countries,  where  these  insects  are 
responsible  for  the  spread  of  some  of  the  most  prevalent  and  dreaded  infections 
of  man.  We  have  already  reviewed  the  relation  of  mosquitoes  belonging  to 
the  Anophelinae  to  malaria;  in  addition  we  now  know  that  Filaria  bancrojti  is 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  63 

transmitted  by  Culex  fatigans,  as  proven  by  Manson  and  others;  Filaria  phili- 
pinensis  by  Culex  fatigans,  proven  by  Ashburn  and  myself;  that  dengue  is 
transmitted  by  Culex  fatigans,  as  shown  by  Graham  and  Ashburn  and  the 
writer;  and  that  yellow  fever  is  alone  transmitted  by  Stegomyia  calopus,  as  con- 
clusively proven  by  the  U.  S.  Army  Board  composed  of  Reed,  Carroll,  Lazear, 
and  Agramonte.  It  is  not  improbable  that  further  research  will  show  that 
these  insects  are  responsible  for  the  transmission  of  still  other  diseases,  but 
enough  is  known  of  their  activity  in  this  respect  to  make  a  knowledge  of  them  of 
great  importance  to  the  medical  practitioner.  In  the  preparation  of  this  sum- 
mary of  our  knowledge  regarding  mosquitoes  I  am  greatly  indebted  to  the  works 
of  Theobald  and  Giles  and  much  of  the  material  included  is  copied  almost 
verbatim  from  their  contributions. 

Of  the  Culicidae,  the  sub-family  Anophelinae  is  the  only  one  of  interest 
to  the  student  of  malaria,  as  only  mosquitoes  belonging  to  this  sub-family  have 
been  proven  to  transmit  malarial  fevers. 

General  Description  of  Anophelinae. — The  following  description 
applies  to  mosquitoes  in  general,  as  regards  anatomical  structure,  and  includes 
only  those  points  of  value  in  diagnosis  or  that  are  essential  to  a  clear  under- 
standing of  the  relation  of  these  insects  to  the  transmission  of  malaria. 

External  Anatomy  of  the  Mosquito. — The  mosquito  is  divided  into 
three  well-marked  areas  for  purposes  of  description:  the  head,  the  thorax, 
and  the  abdomen. 

The  Head. — The  head  varies  somewhat  in  form  in  different  species,  and 
presents- upon  each  side  a  prominent  compound  eye,  larger  in  the  males  than  in 
the  females.  The  space  separating  the  eyes  above  is  known  as  the  occiput,  and 
that  separating  the  eyes  in  front  the  vertex;  the  back  of  the  head  is  the  nape 
or  neck.  The  occiput  and  vertex  are  of  importance  in  classification  on  account 
of  the  scales  and  bristles  with  which  they  may  be  covered.  A  process  projects 
forward  from  the  head  which  is  called  the  clypeus,  and  which  varies  in  structure 
in  different  species.  The  mouth,  or  proboscis,  is  prolonged  forward  into  a 
hollow  tube,  fitted  both  for  piercing  and  sucking,  and  is  composed  of  the  labrum, 
epipharynx,  or  upper  lip ;  two  sharp  lancets  or  mandibles;  the  hypopharynx;  and 
the  labium  or  lower  lip,  which  terminates  in  two  jointed  organs  known  as  the 
lab  ell  a. 

The  hypopharynx  and  the  labrum  form  the  sucking  tube  through  which 
the  blood  is  drawn  when  the  insect  feeds;  the  hypopharynx  is  pierced  by  the 
salivary  duct  through  which  the  saliva  flows  into  the  sucking  tube  and  thence 
into  the  wound.  The  palpi  arise  close  to  the  proboscis,  one  on  either  side,  and 
vary  in  size,  shape,  and  the  number  of  segments  composing  them.  In  the 
Anophelinae  they  are  as  long  as  the  proboscis  in  the  female,  thus  serving  to 
distinguish  them  from  the  mosquitoes  of  the  sub-family  Culex,  in  which  the 
palpi  in  the  female  are  very  short.  The  antennae  also  arise  from  the  head, 
beside  the  palpi,  and  are  long  jointed  structures  surrounded  by  hairs  in  the 
female,  but  in  the  male  terminate  in  minute  plumes. 


64 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 


The  Thorax. — The  thorax  is  situated  between  the  head  and  the  abdomen, 
and  is  composed  of  the  mesotkorax,  the  scutellum,  the  prothoracic  lobes,  and  the 
posterior  portion  or  metatkorax.  The  greater  portion  of  the  thorax  is  comprised 
in  the  mesothorax,  having  posteriorly  a  small  area  called  the  scutellum,  which 
n  the  Anopliclinac  has  a  rounded  border,  while  in  the  other  families  it  is  tri- 
lobed.  The  prothoracic  lobes  are  placed  laterally,  while  the  metathorax  is 
situated  most  posteriorly,  is  rounded  in  contour,  and  placed  beneath  the 
scutellum.  The  thorax  is  of  importance  in  classification  because  of  the 
character  of  the  scales  which  cover  it. 

The  Wings. — The  wings  arise  from  the  upper  portion  of  the  thorax, 
are  two  in  number,  and  their  venation  is  of  great  importance  in  classification. 
Fig.  15  gives  the  venation  of  the  wing  common  to  all  mosquitoes,  and  the  fork 
cells,  A  and  B,  are  of  the  greatest  importance  in  distinguishing  sub-families 
and  genera. 


Fig.  14. — Comparison  of  head  of  female  Anopheles  and  Culex. 
1,  Head  of  Anopheles,  showing  the  palpi  closed  along  the  proboscis;  2,  Head  of  Anopheles, 
showing  the  equal  length  of  the  palpi  and  the  proboscis;  3,  Head  of  Culex,  showing  the  short 
palpi. 


The  Legs. — The  legs  arise  from  the  pro-,  meso-,  and  metathorax,  and 
are  six  in  number.  They  are  of  but  little  value  in  classification  and  will  not, 
therefore,  be  further  described. 

The  Abdomen. — The  abdomen  is  composed  of  eight  well-defined  segments. 
In  the  male  the  last  segment  terminates  in  the  genital  organs,  and  in  the  female 
in  two  lobes.  Scales  clothe  this  portion  of  the  insect  in  most  species,  and  their 
shape  and  arrangement  are  of  great  value  in  differentiation  and  identification 
of  various  species. 

Internal  Anatomy. — To  the  student  of  malaria  the  chief  points  of  interest 
in  the  internal  anatomy  of  the  mosquito  are  situated  in  the  alimentary  canal, 
which  may  be  said  to  commence  at  the  distal  end  of  the  proboscis,  terminating 
at  the  anus.  The  salivary  glands,  really  appendages  of  the  alimentary  canal, 
have  also  to  be  considered  in  this  relation. 

The  Alimentary  Canal. — Commencing  with  the  sucking  tube  of  the 


THE    ETIOLOGY    OF    THE    MALARIAL    LEVERS. 


65 


proboscis,  which  has  opening  into  it  the  salivary  duct,  and  proceeding  backward, 
the  following  structures  are  successively  reached: 

1.  The  true  mouth,  situated  just  behind  the  clypeus. 

2.  The  buccal  cavity. 

3.  The  pharynx,  or  pumping  organ,  by  winch  the  insect  is  enabled  to 
suck  blood  or  other  fluids. 

4.  The  oesophagus,  extending  from  the  pharynx  to  the  oesophageal 
valve;  three  blind  tubules  or.  sacs  diverge  from  the  oesophagus  and  serve  as 
receptacles  for  food. 

5.  The  oesophageal  valve,  which  acts  as  a  valve  between  the  oesophagus 
and  the  mid-gut  or  middle  intestine. 

6.  The  mid-gut,  a  straight  tube  which  terminates  in  a  dilatation. 

7.  The  "stomach."  The  portion  of  gut  between  the  "stomach,"  which  is 
situated  at  the  level  of  the  6th  abdominal  segment  and  the  anus,  is  known 
as  the  hind  gut. 


Fig.  15. — -Venation  of  Wing  in  Anophelinae. 
1  to  6,  First  to  six  longitudinal  veins;  A,  first  sub-marginal  cell  (first  fork-cell);  B,  second 
posterior  cell  (second  fork-cell.);  C,  sub-costal  cell;  D,  marginal  cell;  E,  second  sub-marginal 
cell;  F,  first  posterior  cell;  G,  third  posterior  cell;  H,  anal  cell;  I,  auxiliary  cell:    The  fork-cell; 
A  and  B,  are  of  especial  importance  in  classification.     (Modified  from  Theobald.) 


The  Malpighian  tubes,  arising  from  the  hind-gut,  as  well  as  the  ovaries 
in  the  female,  and  their  appendages,  and  the  genital  organs  of  the  male  will  not 
be  described,  as  they  are  of  little  interest  in  classification  or  in  the  differen- 
tiation of  species. 

The  Salivary  Glands. — The  salivary  glands  are  of  great  interest  because 
through  them  are  transmitted  the  sporozoites  causing  malarial  infection  in  man. 
As  has  been  stated,  the  groove  in  the  sucking  tube  is  connected  with  the  salivary 
glands  by  the  salivary  duct,  at  the  base  of  the  hypopharynx  is  placed  a  pumping 
organ  controlled  by  voluntary  muscles,  and  it  is  by  means  of  this  organ  that 
the  saliva  is  forced  into  the  proboscis  and  thence  into  the  wound.  The  common 
salivary  duct  passes  backward  underneath  the  buccal  valve  and  divides  into 
two  tubes  which  pass  backward  through  the  neck  into  the  thorax  where  they 
connect  the  two  salivary  glands.  Each  of  the  salivary  glands  consists  of  three 
5 


66 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 


blind  caeca,  lined  with  large,  granular  cells,  and  possessing  a  central,  well- 
defined  canal,  opening  into  the  thoracic  branches  of  the  common  duct,  previ- 
ously mentioned.  It  is  in  these  cells  that  the  malarial  sporozoites  are  found  at 
the  termination  of  the  mosquito  cycle  of  development  of  the  plasmodia. 

Life  History  of  the  Anophelinae. — The  Anophelinae,  in  common  with 
all  mosquitoes,  pass  through  a  larval  and  pupal  stage  before  development  into 
the  perfect  insect  and  these  stages  in  their  life  history  are  always  passed  in  water 
so  far  as  we  at  present  know.  I  have  several  times  observed  Anopheles  larvae 
in  semi-fluid  mud,  and  it  is  probable  that  development  can  occur  in  such  an 
environment,  provided  enough  moisture  is  retained  by  the  soil. 

The  Ova. — The  eggs  of  the  Anophclinae  are  deposited  upon  the  surface 
of  water,  and  are  arranged  separately,  and  not  in  boat-shaped  masses  as  in 
Cidex.  The  Anopheles  ova  are  easily  recognized  by  their  lateral  floats,  some 
of  which  are  very  beautiful.  The  ova  are  oval  in  shape,  and  hatch  in  from 
one  day,  as  in  Myzomyia  ludlowii,  to  several  days,  as  in  other  species. 


Fig.  16.  — Internal  Anatomy  of  the  Anophelinae. 
A,  Pharynx;  B,  oesophagus;  C,  dorsal  reservoirs;   D,  oesophageal  valve;  and  caeca;  E, 
beginning  of  mid-gut;  F,  mid-gut;  G,  Malpighian  tube;  H,  stomach;  I,  mid-gut  ends;   J, 
ileum;  K,  colon;  L,  rectum;  M,  anus;  N,  ventral  reservoir;  O,  salivary  glands;  P,  salivary 
duct.     (After  Nuttall  and  Shipley.) 

The  Larvae. — The  larvae  of  all  mosquitoes  are  either  siphonate  or  asi- 
phonate.  The  asiphonate  larvas  always  belongs  to  the  Anophelinae,  and  live 
only  in  water,  either  fresh  or  salt.  It  may  be  said  with  certainty  that  any  of  the 
larvae  of  the  Anophelinae  will  develop  in  any  collection  of  water,  although 
certai-i  species  breed  by  preference  in  certain  localities.  Theobald  states  that 
"practically  all  kinds  of  collections  of  water  are  acceptable  to  the  larvae;  some 
prefer  rain-water  barrels,  cisterns,  and  the  water  in  tins,  calabashes,  and 
jam-pots;  others  ponds,  slow-running  streams,  and  along  the  banks  of  large 
rivers;  others  live  in  the  water  collected  in  bromelias,  and  in  the  water  that 
collects  in  hollow  bamboos,  gaining  their  e  ltrance  through  exit  holes  left  by 
boring  insects.  The  domestic  forms  which  are  best  known  usually  choose 
barrels  and  cisterns.  The  importance  of  the  sylvan  species  is,  however,  just 
as  great,  as  it  is  by  means  of  these  that  fever  is  contracted  in  the  jungle  as  well 
as  in  the  habitations  of  man." 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 


67 


At  Camp  Stotsenburg,  the  most  malarial  post  in  the  Philippine  Islands, 
Anophles  larvae  were  repeatedly  found  in  hollow  bamboo  posts,  as  well  as  in 
small  stagnant  collections  of  water  around  the  native  huts,  thus  proving  con- 
clusively that  the  old  idea  that  Anopheles  breed  only  in  clear,  running  water  is 
incorrect.  It  is  noteworthy,  however,  that  Anopheles  larvae  were  only  found  in 
bamboo  posts  which  allowed  the  ingress  of  sunlight  by  reason  of  being  open  at 
the  top,  while  in  posts  in  which  the  opening  was  so  placed  as  to  exclude  sunlight 
only  Culex  larvae  were  found. 

The  larvae,  like  the  adult  insect,  is  divided  into  three  main  portions,  the 
head,  the  thorax,  and  the  abdomen.  While  in  Culex  the  head  is  larger  than  the 
thorax  and  projects  laterally,  in  the  Anophelinae  the  head  is  smaller  and  the 
thorax  projects  laterally  beyond  the  boundary  of  the  head.  The  thorax  pre- 
sents upon  each  side  bunches  of  bristles  and  is  unsegmented.  The  abdomen 
is  composed  of  nine  segments.     While  in  Culex    Stegomyia,  etc.,  the  eighth 


Fig.  17. — Ova  of  Mosquitoes. 
1  and  2,  Ova  of  M.  culicifacies  (Anopheles);  3  and  4,  Ova  of  N.  maculipalpis  (Anopheles), 
(Note  the  lateral  floats  on  the  Anopheles  ova);  5,  Ova  of  Culex;  6,  Ova  of  Stegomyia. 


abdominal  segment  presents  upon  its  dorsal  surface  a  well-marked  respiratory 
siphon,  in  the  Anophelinae  this  is  represented  by  two  slightly  raised  openings, 
which  are  used  for  respiration,  but  which  do  not  in  the  least  resemble  the 
siphon  of  Culex  or  of  other  species.  The  arrangement  of  the  respiratory  apara- 
tus  of  the  Anophelinae  forces  the  members  of  this  sub-family  to  lie  horizontal 
to  the  surface  of  the  water  during  respiration,  instead  of  at  an  angle,  as  in 
Culex,  and  this  serves  as  an  easy  method  of  differentiating  them.  An  exception 
to  this  rule  has  been  noted  in  a  few  Culicinae.  The  color  of  the  larvae  is 
usually  gray,  brown,  or  greenish.  Anopheles  larvae  are  not  very  resistant  and 
are  usually  short  lived  although  a  few  species  have  been  known  to  hibernate 
through  a  long  winter.  The  length  of  the  larval  stage  varies  in  the  different 
species.     In  Myzomyia  ludlowii  the  larval  stage  occupies  from  9  to  10  days. 


68 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 


The  Pupae. — The  pupal  stage  lasts  from  a  few  hours  to  several  days, 
depending  upon  the  temperature.  During  this  time  the  pupae  are  very  active, 
constantly  coming  to  the  surface  of  the  water  to  breathe,  but  as  they  are  not 
easily  differentiated  from  the  pupae  of  Culex,  a  detailed  description  is  not  con- 
sidered necessary.  Fig.  19  gives  a  good  general  idea  of  the  structure  of  the 
pupa. 

The  Imagine. — When  the  time  has  arrived  for  the  emergence  of  the 
imagine    or  adult  insect,  the  pupa  rises  to  the  surface  of  the  water,  the  skin  over 


Fig.  18. — -Larva  of  Anopheles  and  Culex. 
1,  Larva   of   Anophelinse.     Note  horizontal  position  in  reation  to  surface  of   the  water, 
and  the  absence  of  syphon  (A) .  Larva  of  Culex.     Note  angular  position  in  relation  to  surface 
of  the  water,  and  presence  of  the  syphon,  at  A.     (Fig.  1,  after  Howard;   2,  after  Theobald.) 


the  thorax  breaks  open,  and  the  perfect  insect  gradually  emerges  from  the  pupal 
case,  which  serves  as  a  resting  place  for  it  until  its  wings  are  dried  and  it  is  able 
to  take  flight. 

Habits  of  the  Anophelinae.  Feeding. — As  a  rule,  all  Anophelinae  are 
night  feeders,  but  it  is  not  at  all  unusual  to  observe  Anopheles,  of  various  species, 
feeding  in  the  late  afternoon,  and  I  have  often  seen  Myzomyia  funesta  biting  in 
the  early  morning  and  even  at  noon  in  the  tropics.  During  the  daytime  most 
Anopheles  hide  in  the  woods  or  beneath  the  leaves  of  bushes  and  small  trees  or 
in  dark  corners  of  houses  or  native  huts  in  the  tropics.  I  have  observed  hun- 
dreds of  Myzomyia  ludlowii  and  Myzorhynchus  barbirostris  around  the  base- 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  69 

board  of  toilet  sinks  and  upon  clothing  in  dark  closets  during  the  daytime  in 
the  Philippines.  It  is  undoubtedly  true  that  the  vast  majority  of  mosquitoes 
never  attack  man,  feeding  upon  fruit  and  vegetable  juices,  especially  upon  the 
juices  of  fruits,  as  the  banana,  and.  upon  flowers,  only  attacking  man  as  the  op- 
portunity offers  and  when  convenient.  The  males  are  not  blood  suckers,  but 
subsist  entirely  upon  the  juices  of  fruits  and  flowers.  As  the  females  alone 
feed  upon  blood  it  was  for  a  long  time  supposed  that  this  was  essential  to  the 
laying  of  eggs,  but  later  observations  have  shown  that  this  is  not  so,  and  Theo- 
bald says:  "it  may  therefore  safely  be  said  that  mosquitoes  breed  mainly  with- 
out the  stimulus  of  human  blood."  Many  species  have  been  observed  sucking 
the  blood  of  invertebrates,  such  as  insects. 

Flying  DisTANCE.-^Mosquitoes  do  not  cover  very  great  distances  in 
flying.  Formerly  it  was  supposed  that  the  limit  of  flying  distance  for  mos- 
quitoes was  a  half-mile,  but  it  is  now  known  that  this  distance  is  exceeded  very 
commonly,  and  Theobald  gives  the  average  flying  distance  as  one  mile.  I  am 
sure,  from  personal  observation  in  the  Philippine  Islands,  that  Anopheles 
mosquitoes  often  fly  from  two  to  two  and  a  half  miles  in  search  of  food,  for 
at  Camp  Stotsenburg  no  breeding  places  of  Anopheles  existed  in  the  post 
proper,  so  far  as  we  could  determine,  and  the  nearest  breeding  places  discovered 
were  at  least  two  miles  away;  yet,  at  times,  Anopheles  were  very  numerous  in 
the  post  and  malaria  was  very  prevalent. 

Resting  Position. — The  position  assumed  by  the  insect  while  resting  has 
always  been  used  as  a  differential  point  in  the  classification  of  mosquitoes. 
Regarding  this  it  may  be  said  that  all  of  the  Anophelinae  (with  the  exception, 
according  to  Giles,  of  Myzomyia  culicifacies)  when  at  rest  form  a  complete 
angle  to  the  resting  surface,  the  proboscis,  head,  thorax,  and  abdomen,  being  in 
a  straight  line,  while  in  Culex  the  proboscis,  head  and  thorax,  form  an  angle 
with  the  abdomen,  thus  giving  the  insect  a  hunchback  appearance  (see  Fig.  20). 

Hibernation. — In  the  tropics  mosquitoes  breed  throughout  the  entire 
year,  but  are  much  less  numerous  in  the  dry  than  in  the  rainy  season.  In 
temperate  and  cold  regions  they  may  pass  through  the  cold  season  as  fully 
developed  adults,  as  larvae,  or  even  in  the  ova.  According  to  Theobald,  the 
fertilized  females  of  A .  maculipennis  hibernate  in  the  adult  stage  in  cellars,  out- 
houses, stables,  etc.,  while  A.  bifurcatus  and  A.  nigripes  exist  throughout  the 
winter  in  the  larval  stage  even  under  thick  ice.  If  a  warm  spell  occurs  during 
a  winter  some  of  the  hibernating  mosquitoes  emerge  from  their  hiding  places 
and  bite,  thus  causing  outbreaks  of  malaria  during  the  winter  season.  It  is 
also  true  that  the  ova  of  some  species  of  Anopheles  will  withstand  a  considerable 
amount  of  drying,  and  I  have  not  infrequently  observed  the  development  of 
larvae  in  dry  mud  which  has  been  placed  in  water  and  protected  from  outside 
contamination.  In  the  tropics  I  believe  that  many  species  of  Anopheles  would 
disappear  if  it  were  not  for  the  resisting  powers  of  the  ova  to  drying  and  sun- 
light, and  that  it  is  this  property  which  enables  these  insects  to  exist  through  the 
dry  season  in  areas  in  which  water  is  almost  absent.     Just  as  in  the  temperate 


70  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

and  cold  regions  these  insects  are  able  to  resist  freezing,  so  in  the  tropics  nature 
has  provided  them  with  ample  resisting  powers  against  drying  and  the  effects  of 
the  tropical  sun. 

Classification. — The  classification  adopted  in  this  work  is  that  of 
Theobald,  a  classification  which  has  been  accepted  by  nearly  every  scientific 
worker  upon  mosquitoes,  such  as  Blanchard,  Daniels,  Ludlow,  Graham,  Lutz, 
and  Goeldi.  This  classification  is  based  largely  upon  the  character  of  the 
scales  which  clothe  the  head,  thorax,  wings,  and  abdomen  of  the  insects. 
Fig.  21  illustrates  the  shape  and  variation  in  these  scales  as  given  by  Theobald 
and  also  gives  the  nomenclature  applied  to  them. 

The  general  characteristics  of  the  sub-family  Anophelinae,  as  given  by 
Theobald,  are  as  follows:  Head,  numerous  upright  forked  scales.  Thorax 
scaly  or  hairy,  metanotum  always  nude,  scutellum  always  simple,  with  scales 
or  hairs.  Abdomen  hairy  or  scaly.  Palpi  in  the  female  as  long  as  the  probos- 
cis. Wings,  long  fork  cells,  the  first  submarginal  longer  than  the  second 
posterior  cell.  Up  to  the  present  time  Theobald  has  described  18  genera  of 
Anophelinae,  but,  while  it  is  probable  that  each  genus  contains  species  which 
are  able  to  transmit  malaria,  only  a  few  of  the  genera  are  at  present  of  interest  to 
us  in  this  relation.  Of  the  18  genera,  eight  are  represented  by  but  a  single 
species,  and  none  of  these  have  been  proven  to  transmit  malaria.  These 
genera  are  Feltinella;  Bironella;  Aldrichia;  Chagasia;  Chrystya;  Kerteszia; 
Myzorhynchella  and  LopJwscelomyia. 

For  the  differentiation  of  the  other  genera  Theobald  gives  the  following 
table: 

A.  Fork  cells  long. 

a.   Thorax  and  abdomen  with  hair-like  curved  scales. 

a.  Head  with  upright  forked  scales  only. 

i.  Wing  scales  large  and  lanceolate,  wing  unspotted,  or  if  spotted 
the  spots  due  to  collections  of  similarly  colored  scales.  Genus, 
Anopheles.      Meig. 

2.  Wing  scales  small,  narrowly  lanceolate,  the  wings  with  spotting 
of  varied  color.      Genus,  Myzomyia.      Bl. 

3.  Wings  with  patches   of    large    inflated   scales.      Genus,   Cyclo- 

leppteron.      Theo. 
/?.    Median  area  of  head  with  some  flat  scales.      Genus,     Stethomyia. 
Theo. 

b.  Thorax    with    narrow    curved    scales;    abdomen  hairy;  wing  scales 

small  and  lanceolate.      Genus,   Pyretophorus.      Bl. 

c.  Thorax   with  hair-like  curved  scales  and  some  narrow  ones  in  front ; 

abdomen  with  apical  lateral  scale  tufts  and  scaly  venter;  no  ven- 
tral tuft;  wing  scales  lanceolate.      Genus,  Arribalzagia.      Theo. 

d.  Thorax   with   hair-like   curved  scales;  no  lateral  abdominal  tufts;  a 

distinct  apical  ventral  tuft  and  dense  scales  palpi  in  the  female; 
wings  with  dense,  large,  lanceolate  scales.  Genus,  Myzorhynchus. 
Bl. 

e.  Thorax   and   abdomen   with    scales;    thoracic    scales   narrow-curved 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  7 1 

or   spindle-shaped;    abdominal   scales   as   lateral    tufts   and   dorsal 
patches  of  flat  scales.      Genus,  Nyssorhynchtts.      Bl. 

f.  Abdomen   nearly  completely  scaled  with    long    irregular  scales  and 

with  lateral  scale  tufts.     Genus,  Celha.     Theo. 

g.  No  lateral  tufts  and  smaller  wing  scales.      Genus,  Neocellia:     Theo. 

The  following  brief  descriptions  of  the  principal  genera  of  interest  to 
students  of  malaria  are  largely  those  given  by  Theobald,  to  whom  I  am  indebted 
for  much  that  appears  in  this  chapter  upon  mosquitoes. 

Genus,  Anopheles.  Meigen,  1818.  Occurs  mostly  in  temperate  regions, 
although  certain  species  occur  in  tropical  countries,  especially  in  the  hill  regions. 
This  genus  is  found  in  Europe,  the  United  States,  North  Africa,  hill  districts 
of  India,  in  Australia,  West  Indies,  West  Africa,  all  of  North  America.  Fifteen 
species  are  included  in  this  genus,  the  type  species  being  A.  maculipennis,  a 
common  species  in  Europe  and  North  America.      Some  of  the  species  have  been 


Fig.  19. — Pupa  of  Anophelinae.     (After  Nuttall  and  Shipley.) 

proven  to  transmit  malaria,  as  A.  maculipennis  and  A.  algeriensis.  The 
larvae  of  A.  maculipennis  occur  in  water  barrels  and  pools,  others  in  small  natural 
collections.  Adult  A.  maculipennis  hibernate.  Theobald  believes  that  all 
species  may  act  as  the  hosts  of  the  malarial  plasmodia. 

Genus,  Myzomyia.  Blanchard,  1902.  This  genus  occurs  in  Europe, 
Africa,  Asia,  the  Philippine  Islands,  but  does  not  occur  in  North  or  South  America, 
the  West  Indies,  or  Australia.  The  type  species  is  M.  funesta  Giles,  one  of  the 
most  common  of  malarial  carriers  in  tropical  regions  in  Asia  and. Africa.  Five 
of  this  genus  have  been  proven  to  transmit  malaria,  namely,  M.  listonii  Liston: 
M.  funesta  Giles;  M.  turkhudii  Liston;  M:  culicifacies  Giles,  and  M.  nili  Theobald. 
M.  culicifacies  is  of  especial  interest,  as  its  resting  position  is  like  that  of  non- 
malarial  mosquitoes.  M.  rossii  Giles  has  been  proven  incapable  of  transmitting 
malaria.  These  mosquitoes  vary  greatly  in  their  breeding  habits,  some  breeding 
around  human  habitations,  while  others  are  sylvan  species.  Recently  M.  lud- 
lowii  Theobald,  a  common  species  in  the  Philippine  Islands,  has  been  proven  a 
host  for  the  aestivo-autumnal  plasmodia.  About  twenty-one  species  occur  in 
this  genus. 

Genus,  Stethomyia.  Theobald,  1902.  Contains  but  two  species,  5.  nimba 
Theobald  and  5.  fragilis  Theobald.  The  former  is  probably  the  transmitter  of 
jungle  malaria  in  South  America.  The  latter  occurs  in  the  Federated  Malay 
States. 


72  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

Genus,  Pyretcphorus.  Blanchard,  1902.  Occurs  only  in  Asia,  Africa,  and 
Australia.  They  are  all  large  mosquitoes  and  have  beautifully  spotted  wings. 
The  larvae  live  in  puddles,  streams,  pools,  rice  fields,  and  in  flowing  water. 
Three  species  have  been  proven  to  transmit  malaria:  P.  costalis  Loew;  P. 
chaudoyei  Theobald,  and  P.  ardensis  Theobald.  Over  twenty-six  species  have 
been  described. 

Genus,  Arribalzagia.  Theobald,  1902.  Only  one  species  belongs  to  this 
genus,  A.  maculipes  Theobald.  This  species  occurs  in  the  Brazils  and  is  prob- 
ably a  transmitter  of  malaria. 

Genus,  Myzorhynchus.  Blanchard,  1902.  This  genus  is  distinguished 
by  the  densely  scaled  palpi,  hairy  thorax,  and  densely  scaled  proboscis.  They 
are  all  large  dark  insects,  breeding  in  swamps,  and  beneath  tropical  vegetation. 
They  occur  in  South  Europe,  Asia,  Africa,  and  Australia.  Four  species  have  been 
found  in  the  Philippine  Islands. 

Genus,  Nyssorchynchus.  Blanchard,  1902.  About  twenty  species  occur 
in  this  genus.  Mosquitoes  of  this  genus  are  generally  house  breeders  or  develop 
in  pools  or  puddles  in  close  proximity  to  human  habitations.  They  occur  in  India 
Africa,  Australia,  and  in  the  Philippine  Islands.  N.  stephensii  has  been  proven 
to  act  as  a  host  for  the  malarial  plasmodia. 

Genus,  Cellia.  Theobald,  1903.  Seven  species  occur  in  this  genus,  the 
most  marked  characteristics  being  the  scaled  abdomen  with  dense  lateral  tufts, 
and  the  heavily  scaled  wings.  The  larvae  live  in  any  open  water  and  some 
species  are  commonly  found  in  human  habitations.  The  following  species  have 
been  found  to  harbor  the  malarial  plasmodia.  C.  argyrotarsis,  C.  albimanus,  and 
C.  pharoensis. 

For  a  detailed  description  of  the  species  mentioned  in  the  foregoing 
summary  the  reader  is  referred  to  Theobald's  monographs  upon  the  Culicidae. 

Geographical  Distribution  of  Mosquitoes. — Mosquitoes  occur  where- 
ever  malaria  does,  but  it  does  not  follow  that  malaria  is  always  present  even 
though  mosquitoes  are  abundant.  In  order  that  the  malarial  fevers  may 
spread  in  any  locality,  the  right  species  of  mosquitoes  must  be  present,  together 
with  individuals  infected  with  some  species  of  the  plasmodia.  To  the  student 
of  malaria,  the  geographical  distribution  of  mosquitoes  resolves  itself  into  the 
determination  of  the  distribution  of  the  Anophelinae  only,  and,  as  has  been  said, 
the  distribution  of  malaria  and  that  of  mosquitoes  belonging  to  this  sub-family 
exactly  coincide,  and  the  amount  of  malaria  in  any  country,  or  in  any  given 
locality  is  an  index  of  the  number  of  Anopheles  present.  This  fact  is  of  impor- 
tance from  a  prophylactic  standpoint,  as  the  determination  of  the  species  of 
mosquito  present  in  any  locality  enables  us  to  avoid  those  inhabited  by 
Anopheles  or  to  take  the  proper  precautions  against  infection.  In  the  selection 
of  camp  sites  of  a  more  or  less  permanent  character  or  of  the  sites  for  permanent 
military  posts,  a  preliminary  "mosquito  survey"  will  often  prove  of  inestimable 
value,  both  as  regards  the  future  health  of  the  camp  or  post  and  the  cost  of 
maintaining  it.  The  same  is  true  of  the  selection  of  building  sites  of  any 
character  where  mosquitoes  and  malaria  are  apt  to  be  present.  I  have  already 
spoken  of  the  geographical  distribution  of  the  malarial  fevers,  and  it  is  not,  there- 
fore, necessary  to  give  in  detail  the  countries  in  which  the  malarial  mosquitoes 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  73 

occur,  as  to  do  so  would  be  but  a  repetition  of  what  has  already  been  said  regard- 
ing the  distribution  of  malaria.  It  may  be  of  value,  however,  to  mention  those 
species  of  the  Anophelinae  which  have  been  proven  by  experiment  to  transmit 
the  malarial  fevers,  and  to  mention  the  countries  in  which  such  species  occur, 
with  special  reference  to  the  West  Indies,  the  United  States,  and  the  Philippine 
Islands. 

The  following  members  of  the  sub-family  Anophelinae  have  been  found 
experimentally  to  transmit  the  malarial  fevers  or  to  act  as  hosts  of  the  malarial 
plasmodia: 

Genus,  Anopheles.  A.  maculipennis,  Meig;  A.  bifurcatus,  Linn;  A.  algeri- 
ensis,  Theo.  ;  A.  jasoensis,  Tsuzuki;  A.  formosaensis,  Donne;  A.  cohaesus, 
Donne;  A.  quadrimaculatus ,  Say;  A.  albipes,  Giles;  A.  vagus;  A.vincenti;  A. 
martini;  A.  pursati.      12  species. 

Genus,  Myzomyia.  M.  listoni,  Liston;  M.  fnnesta,  Giles;  M.  turkhudii, 
Liston;  M.  culicifacies,  Giles;  M.  nili,  Theo. ;  M.  his paniola,  Theo.;  M.lud- 
lowii,  Theo.  ;  M.  lutzii,  Theo.     8  species. 

Genus,  Stethomyia.     S.  nimba,  Theo.      i  specie. 

Genus,  Pyretophorus.  P.  costalis,  Loew;  P.  chaudoyei,  Theo.;  P.  ardensis, 
Theo.;  P.  superpictus,  Grassi;  P.  jeyporensis,  Theo.      5  species. 

Genus,  Arribalzagia.      A.  maculipes,  Theo.      i  specie. 

Genus,  Myzorhynchus.  M.  sinensis,  Wied;  M.  barbirostris,  Van  der  Wulp; 
M.  pseudopicius,  Grassi;  M.  pahidis;  Theo.;  M.  mauritianus,  Grandpre  and 
Charmoy;  M.  coustanii,  Lav.      6  species. 

Genus,  Nyssorhynchus.  N.  fuliginosus,  Giles;  N.  stephensii,  Liston;  N. 
maculipalpis;  Giles,  N.  theobaldii,  Giles.     4  species. 

Genus,  Cellia.  C.  argyrotarsis,  Robineau-Desvoidy;  C.  pharoensis,  Theo.; 
C.  albimanus,  Wied.      3  species. 

From  the  above  summary  it  will  be  seen  that  no  less  than  forty  species 
of  the  Anophelinae  have  been  proven  experimentally  to  be  hosts  of  the  malarial 
plasmodia.     The  geographical  distribution  of  these  species  is  as  follows: 

West  Indies. — Cellia  argyrotarsis.      Cellia  albimanus. 

Canada. — Anopheles  maculipennis. 

United  States. — Anopheles  maculipennis.  Anopheles  quadrimaculaius . 
Cellia  argyrotarsis. 

Central  and  South  America. — Anopheles  albipes.  Arribalzagia  maculipes. 
Pyretophorus  lutzii.      Cellia  argyrotarsis.      Myzomyia  lutzii.      C.  albimanus. 

Europe. — Anopheles  maculipennis.  Anopheles  bifurcatus.  Myzorhynchits 
pseudopicius.     Pyretophorus  superpictus.      Myzomyia  hispaniola. 

Asia. — India. — Myzomyia  culicifacies.  Myzomyia  hstonii.  Myzomyia  turk- 
hudii. Pyretophorus  jeyporensis.  Myzorhynchus  barbirostris.  Myzorhynchus 
sinensis.  Nyssorhynchus  theobaldi.  Nyssorhynchus  stephensii.  Nyssorhynchus 
fuliginosus.     Nyssorhynchus  maculipalpis. 

Japan. — Anopheles  jesoensis.     Anopheles  formosaensis.     Anopheles  cohaesus. 

Africa. — Myzomyia  funesta.  Myzomyia  nili.  Pyretophorus  costalis.  Pyre- 
tophorus ardensis.  Pyretophortis  chaudoyei.  Myzorhynchus  barbirostris.  Myzor- 
hynchus mauritianus.      Myzorhynchus  paludis.      Cellia  pharoensis. 


74 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 


Madagascar. — Myzorhynchus  coustanii. 

Mauritius. — Myzorhynchus  mauritianus. 

The  Philippine  Islands. — -The  following  malarial  mosquitoes  have  been 
found  in  the  Philippine  Islands  by  Ludlow,  Whitmore,  Banks,  and  the  writer: 
Myzomyia  funesta.  Myzomyia  ludlowii.  Myzorhynchus  barbirostris.  Myzor- 
hynchus sinensis.     Nyssorhynchus  fuliginosus. 

Further  observation  will  undoubtedly  demonstrate  that  other  species  occur 
in  these  islands. 

Number  of  Infected  Mosquitoes  in  Malarial  Regions. — The  number 
of  mosquitoes  showing  infection  in  malarial  regions  will  depend  upon  the 
number  of  infected  individuals  present,  the  season  of  the  year,  certain  atmos- 
pheric conditions,  and  the  amount  of  care  exercised  by  the  inhabitants  in  protect- 
ing themselves  from  these  insects.  Thus  the  figures  given  by  various  observers 
differ  very  greatly  in  this  respect,  as  would  be  expected. 


Fig.  20. — Comparison    of  Resting  Position  of  Anopheles  and  Culex. 
1,  Resting  position  of  Culex,  on  vertical  surface;  2,  resting  position  of  Anopheles  on  vertical 
surface.     (The  resting  position  upon  a  horizontal  surface  may  be  observed  by  turning  the 
page  so  that  the  vertical  line  becomes  horizontal.) 


Celli,  in  Italy,  found  that  of  the  Anopheles  examined  by  him,  2.5  per  cent, 
were  infected  with  the  malarial  plasmodia;  A.  Plehn,  in  Kamerun,  examined 
860  Anopheles  and  found  2.2  per  cent,  infected;  La  Monaco  examined  1,420 
Anopheles  and  found  1  in  164  infected  during  August,  and  3  in  103  infected 
in  September;  Sargent,  in  Algiers,  found  1.6  per  cent,  of  the  Anopheles  which 
he  examined  infected,  and  Zieman,  in  Africa,  found  that  of  the  mosquitoes  col- 
lected in  the  huts  of  the  natives  no  less  than  16.6  per  cent,  showed  infection 
with  malarial  plasmodia. 

At  Camp  Stotsenburg,  in  the  Philippine  Islands,  during  the  height  of  the 
malarial  season,  as  high  as  35  per  cent,  of  the  Anopheles  examined  have  shown 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 


75 


infection,  but  at  other  times  the  percentage  has  been  very  small,  sometimes 
less  than  i  per  cent. 

Daniels  found  that  47.5  per  cent,  of  the  mosquitoes  which  he  allowed  to 
bite  malarial  patients  became  infected. 

It  is  now  a  well-established  fact  that  certain  of  the  Anophelinae  are  incapable 
of  acting  as  hosts  to  the  malarial  plasmodia,  and  the  following  observations  of 
Stephens  and  Christophers  and  of  Hirshberg  are  of  interest  in  this  connection. 

Stephens  and  Christophers,  at  Mian  Mir,  India,  dissected  259  Myzomyia 
culicifacies,  and  found  12  or  4.6  per  cent,  infected  with  malarial  sporozoites; 
of  496  Myzomyia  rossii  dissected  by  them  not  one  was  found  infected.     At 


Fig.  21. — Character  of  Scales  upon  Mosquitoes. 
1,  2,  3,  and  4,  Upright  forked  scales;  5,  spatulate  scale;  6,  spindle  scale;  7  and  8,  broad  and 
narrow  curved  scales;  9,  linear  scale;  10,  lanceolate  scale;  11  and  12,  hair  scales:  13,  broad 
asymetrical  scale.  14;  ordinary  butterfly  scale. 


Enur,  in  India,  the  same  observers  dissected  69  Myzomyia  culicifacies  and  found 
6  or  8.6  per  cent,  infected  with  sporozoites;  of  364  Myzomyia  rossii  dissected  at 
the  same  time  not  one  was  found  infected. 

Hirshberg,  in  his  experiments,  found  that  out  of  58  Anopheles  puncti- 
pennis,  none  developed  malarial  sporozoites,  while  of  48  Anopheles  maculi- 
pennis,  eight  were  positive  for  sporozoites. 

Not  only  are  some  of  the  Anophelinae  unable  to  act  as  hosts  for  the  plasmodia, 
but  some  species  can  only  act  as  host  for  a  certain  species  of  plasmodia;  this 
fact  has  been  proven  again  and  again  and  serves  to  explain  why  certain  types 
of  malaria  are  limited  to  certain  localities.  In  Japan  it  has  been  found  that 
Anopheles  formosaensis  and  Anopheles  cohaesus  can  only  transmit  the  aestivo- 
autumnal  infections,  while  Anopheles  jesoensis  is  able  to  act  as  a  host  for  both 


76 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 


the  benign  tertian  and  the  aestivo-autumnal  infections.  On  the  other  hand, 
Anopheles  maculipennis,  the  most  common  mosquito  occurring  in  temperate 
regions,  is  able  to  transmit  tertian,  quartan,  and  aestivo-autumnal  malaria. 

While  at  the  present  time  the  malarial  mosquitoes  are  more  or  less  localized 
in  their  distribution  and  certain  types  of  malaria  are  thus  confined  to  limited 
regions,  the  increase  of  transportation  facilities  and  of  commerce  will  inevitably 
lead  to  a  more  general  distribution  of  these  insects,  and  thus  regions  free  from 


:—0 


Fig.  22. — Showing  characteristics  of  Scales  on  various  portions  of  body  of  different  species 
of  the  Anophelinae,  which  have  been  proven  to  transmit  malaria. 

i,  Anopheles;  2,  Myzomyia;  3,  Pyretophorus;  4,  Cellia;  5,  Myzorhynchus;  6,  Nyssorhynchus. 
(Arranged  from  Theobald.) 


malarial  infection  will  become  infected,  and  the  more  severe  types  of  malaria, 
the  aestivo-autumnal,  will  invade  territory  hitherto  infected  with  the  benign 
tertian  type. 

Number  of  Species. — Nearly  1000  species  of  mosquitoes  have  been 
described,  of  which  the  Anophelinae  number  some  150  species.  Most  of  these 
insects  are  wood  dwellers  and  do  not  come  in  contact  with  man,  but  it  is  probably 
true  that  most,  if  not  at  all,  of  the  Anophelinae  which  are  capable  of  transmitting 
the  malarial  fevers  are  semi-domesticated  species,  and  prefer  to  live  within 
reach  of  human  habitations. 


THE    ETIOLOGY    OF    THE    MALARIAL    LEVERS.  77 

Literature  upon  the  Development  of  the  Malarial  Plasmodia  within  the  Mosquito 

and  upon  Mosquitoes. 

Development  of  the  Malarial  Plasmodia  within  the   Mosquito. 
896.      Manson.      The   Life  History  of  the   Malaria  Germ   Outside  the  Human 
Body.      The  Brit.  Med.  Jour.,  Mar.  14,  21,  28,  p.  641,  512,  774. 

896.  Ross,  Ronald.  Observations  on  Malarial  Parasites.  Brit.  Med.  Jour., 
Feb.  1. 

897.  Idem.  On  Some  Peculiar  Pigmented  Cells  Found  in  Two  Mosquitoes 
Fed  on  Malarial  Blood.      Brit.  Med.  Jour.,  vol.  ii,  p.   1786. 

897.  MacCallum.  On  the  Flagellated  Form  of  the  Malarial  Parasite.  The 
Lancet,  No.  13,  p.   1240. 

898.  Ross,  Ronald.  Pigmented  Cells  in  Mosquitoes.  Brit.  Med.  Jour., 
vol.  i. 

898.  Idem.  Report  on  the  Cultivation  of  Proteosoma  Labbe  in  Gray  Mosqui- 
toes.     Calcutta,  May  21,  1898. 

898.  Idem.  The  Role  of  the  Mosquito  in  the  Evolution  of  the  Malarial  Parasite. 
The  Lancet,  vol.   ii,  p.  488. 

898.  MacCallum.  On  the  Haematozoan  Infections  of  Birds.  Jour.  Exper. 
Med.,   Jan. 

899.  Ross,  Ronald.  Life  History  of  the  Parasites  of  Malaria.  Nature,  vol. 
lx,  No.  1553,  p.  322. 

899.      Idem.      Infection  of  Birds  with  Proteosome  by  the  Bites  of  Mosquitoes. 

The  Indian  Med.      Gaz.,  vol.  xxxiv,  Jan.  1. 
899.      Thayer,  W.  S.      Recent. Investigations  upon  Malaria.      Med.  News,  vol. 

lxxiv,  No.  20,  p.  617. 
899.      Bastianelli  and   Bignami.      Sullo  sviluppo    dei   parasiti  della  terzana 

nell'  Anopheles  claviger.      Bull.  d.  R.  Accad.  med.  di  Roma,   Anno  xxv, 

Fasc.  3,  Apr.   19. 
899.     Grassi,    Bignami   and    Bastianelli.     Ulterioti  richerche  sul  ciclo  dei 

parassiti  malarici  umani  nel  corpo  del  zanzarone.      R.  Accad.  dei  Lincei, 

vol.  viii,  8  Gennaio. 
899.      Koch,  R.     Ueber   die    Entwicklung  der  Malaria  parasiten.      Zeitschr.    f. 

Hyg.,  Bd.  xxxii. 
899.      Grassi,  Bignami  and  Bastianelli.      Resoconto  degli  studi  fatti  sulla  mala- 
ria durante  il  mese  di  gennaio.      R.  Accad.  dei  Lincei,  vol.  viii,  Feb.  5. 
899.      Nuttall.      Die     Mosquito-Malaria-Theorie.      Centralbl.     f.     Bakt.,     etc. 

Feb.  14,  21,  28,  and  Mar.  18. 
899.      Daniels.      On  the  Transmission  of  Proteosoma  to  Birds  by  the  Mosquito. 

Proceedings  Royal  Soc,  vol.  lxiv,  p.  443. 

899.  Grassi.  Ancora  sulla  malaria.  R.  Accad.  dei  Lincei,  vol.  viii,  Fasc. 
6,  Sept.  17. 

900.  Ross,  Ronald.  Malaria  and  Mosquitoes.  Nature,  vol.  lxi,  No.  1587, 
p.  522. 

900.  Zeiman.  Zweiter  Bericht  uber  die  Malaria  iind  Moskitos.  Deutsch. 
med.  Woch.,  Nos.  47  and  48. 

900.  Manson.  Experimental  Proof  of  the  Malaria-Mosquito  Theor3T.  The 
Lancet,  p.   923. 

901.  Ross,  Ronald.  Summary  of  Researches  on  the  Propagation  of  Malaria, 
etc.      Brit.  Med.  Jour.,  vol.  i,  p.  193. 

901.      Woldert.      Cultivation   of  the  Aestivo-autumnal  Parasite  in  the  Mos- 
quito.    Jour.  Am.  Med.  Assoc,   No.  9. 
901.      Chatterjee.      Parasites  in  Anopheles.      Indian.  Med.  Gaz.,  p.  371. 


78  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

1902.      Schuffner.      Die     Beziehungen    der   Malariaparasiten    zu    Mensch    und 

Mucke,  etc.  Zeitschr.  f.  Hyg.,  etc.,  vol.  lxi,  p.  89. 
1902.      Schaudinn.      Stu.  ii.   Krankheit.      Protozoen.      Arb.  a.   d.  Kaiserl.  Ges., 

Bd.  xix,  2. 

1902.  Favre.      Die  Beziehung  von  Malaria  zu  Anopheles.      Wratsch,  No.  37. 
1904.      Schaudinn.      Generations-    und    Wirtswechsel    bei    Trypanosomen    und 

Spi'rochaeten  Arb.  a.  d.  Kaiserl.      Gesundheitsamt.      Bd.  xx,  Heft  3. 
1904.      Jancso.  '   Zur  Frage  der  Infektion  der  Anopheles  claviger.,   etc'     Cen- 

tralb.  f.  Bakt.,  Bd.  xxxvi,  p.  624. 
1904.     Galli- Valeric      Sur    la    presence    doocystes    chez   Anopheles.      Lutzi, 

Theobald.     Centralbl.  f.  Bakt.,  Bd.  xxxv,  No.  1. 
1904.     Plehn,  A.      Ergebnisse   der  neuesten  Forschungen  auf  dem  gebiet  der 

Malaria  epidemiologic.      Archiv.  f.  Hyg.,  Bd.  xlix,  p.  1. 

1906.  Zieman.      Malaria.      Mense's  "  Handbuch  der  Tropenkrankheiten,"   Bd. 
iii,  Halb  Bd.  i. 

Literature  upon  Mosquitoes. 

1 90 1  to  1906.      Theobald,  F.  V.      A  Monograph  of  the  Culicidae  of  the  World. 
vol.  i  and  ii,  1901  ;  vol.  iii,  1903  ;  vol.  iv,  1906.      British  Museum,  London. 

1903.  Sergent.      Moustiques  et  maladies  infectieuses.      Encycl.   Scientif.    des 
Aide-Memoires.     Paris. 

1904.  Giles.      Hand-book  of  the  Gnats  or  Mosquitoes,  2d  Ed.,  New  York,  Wm. 
Wood  &  Co. 

1904.  Idem.      A  Revision  of  the  Anophelinae.      (Published  in  above  work.) 

1904.  Felt.      Mosquitoes  or  Culicidae  of  New  York,  Bull.  323,  New  York  State 
Mus. 

1904.  Smith,  J..  B.      Mosquitoes.      Report  New  Jersey  State  Agri.  Station. 

1905.  Blanchard.      Les  Moustiques.     Paris. 

1907.  Howard.     Mosquitoes.     Osier's  "Modern  Medicine,"  vol.  i,  p.  370.    Phil. 
1907.  Theobald.      Mosquitoes  or  Culicidae.     Allbutt  and  Rolleston's  "  System 

of  Medicine,"  vol.  ii,  part  ii,  p.   122,  London. 


CHAPTER  IV. 

Methods  of  Transmission  of  the  Malarial  Plasmodia :  By  the  Atmosphere ;  By 
Water;  By  Inoculation  of  Malarial  Blood;  By  Inoculation  by  the  Mosquito;  Culti- 
vation of  Malarial  Plasmodia ;  Immunity. 

Up  to  within  very  recent  times  it  was  held  by  many  students  of  malaria 
that  the  disease  might  be  transmitted  to  man  in  one  of  three  ways,  either  by  the 
air,  by  water,  or  by  the  bite  of  an  infected  mosquito.  The  theories  of  the 
transmission  of  malaria  by  the  air  or  by  water  are  very  ancient,  and,  until  the 
role  played  by  the  mosquito  in  the  transmission  of  these  fevers  was  discovered, 
both  had  ardent  advocates,  although  there  was  but  little  experimental  evidence 
upon  which  to  base  either  theory,  and  that  little  of  no  scientific  value.  The 
only  method  of  the  transmission  of  malaria  that  has  been  proven  scientifically  is 
that  by  the  bite  of  an  infected  mosquito,  and  at  the  present  time  this  is  the  only 
known  method  of  transmission.  While  it  would,  perhaps,  in  the  light  of  our 
present  knowledge,  be  rash  to  assert  that  the  malarial  fevers  can  be  transmitted 
only  by  the  mosquito,  the  fact  remains  that  no  other  method  of  natural  trans- 
mission has  been  discovered,  and,  therefore,  that  as  far  as  we  can  see,  the 
malarial  fevers  are  only  transmitted  to  man  by  the  bite  of  mosquitoes  belonging 
to  the  Anophelinae.  Before  considering  the  experimental  evidence  upon  which 
the  mosquito  theory  of  the  transmission  of  malaria  is  based,  a  short  review  will 
be  given  of  the  air  and  water  theories  of  transmission. 

Transmission  by  the  Atmosphere. — This  is  the  most  ancient  of  all  of  the 
theories  of  malarial  transmission,  and  it  was  the  belief  in  this  method  that  led  to 
the  term  "malarial"  as  applied  to  these  fevers.  The  advocates  of  this  theory 
believed  that  the  malarial  germs  reached  man  through  the  respiratory  tract, 
being  inhaled,  as  in  dust,  or  from  the  infected  air  of  malarial  regions.  This 
theory  was  accepted  by  multitudes  of  observers,  yet  never  had  a  single  experi- 
mental fact  that  proved  it  or  that  was  of  sufficient  importance  to  serve  as  a 
logical  argument  in  favor  of  such  a  method  of  transmission.  On  the  contrary, 
there  are  many  facts,  well  known  to  the  strongest  adherents  of  this  theory,  that 
conclusively  prove  such  a  method  of  transmission  to  be  impossible.  Among 
these  may  be  mentioned  the  strictly  local  character  of  malarial  infection;  the 
protection  afforded  by  heights;  the  greater  prevalence  of  the  disease  in  moist 
regions  and  during  the  rainy  season,  when  dust  is  not  present;  the  fact  that 
these  fevers  are  not  carried  by  the  wind;  and  the  protection  afforded  the  crews 
of  ships  when  the  ships  are  anchored  at  some  distance  from  the  shore.  To  this 
theory  we  owe  the  common  opinion  that  the  air  of  malarious  localities  is  poison- 
ous; that  the  vapors  and  fogs  arising  from  marshes  and  lowlands  are  laden 

79 


So  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

with  malaria;  and  numerous  other  fanciful  opinions,  which,  even  though  we 
now  know  them  to  be  false,  are  yet  held  by  many,  and  in  some  localities  con- 
stitute a  stumbling-block  whenever  measures  looking  to  the  prophylaxis  of 
malaria  are  a  subject  for  discussion. 

The  strictly  local  character  of  malarial  infections  has  long  been  used  as 
an  argument  against  the  transmission  of  the  disease  by  the  air.  Almost  every 
authority  has  agreed  that  malaria  spreads  but  a  little  way  in  a  horizontal  or 
vertical  direction.  Celli  quotes  a  typical  example  of  this  given  by  Marchiafava 
and  Spadoni.     In  Celli's  words: 

"Near  Sinigaglia  there  is  a  canal  between  the  river  Misa  and  the  sea;  the 
water  stagnating  there  was,  up  till  a  little  time  back,  the  fomites  of  malarial  infec- 
tion. The  inhabitants  of  the  nearest  houses  and  more  especially  of  the  houses 
with  the  doors  and  the  windows  looking  on  this  canal,  suffered  from  malaria, 
while  those  of  the  houses  a  little  more  distant  remained  immune." 

There  are  very  numerous  instances  of  this  kind  in  the  literature  upon  ma- 
laria; Bignami  instances  that  while  the  hospital  of  San  Michele  di  Ripa  Grande 
is  free  from  malaria,  there  are  most  dangerous  malarial  foci  in  the  immediate 
neighborhood  and  that  the  inhabitants  of  Sezze  who  live  near  a  marsh  suffer 
greatly  from  malaria,  while  those  living  near  the  hills  in  the  vicinity  do  not 
suffer  from  the  disease.  Marchiafava  and  Bignami  instance  certain  cities,  as 
Genzano  and  Albano,  situated  between  the  Pontine  Marshes  and  Rome,  as 
disproving  the  theory  of  transmission  by  air,  because,  while  receiving  the 
emanations  from  the  most  deadly  malarial  localities  in  these  marshes,  they  are 
entirely  free  from  malarial  fevers. 

It  has  long  been  known  that  ships  anchoring  a  goodly  distance  off  the  most 
malarial  coasts  escape  infection,  which  would  not  occur  if  the  germ  of  the 
disease  were  carried  by  air  currents.  During  the  campaign  in  Madagascar, 
according  to  Vincent  and  Burot,  the  troops  operating  upon  shore  were  almost 
decimated  by  malaria,  while  the  crews  of  the  war  ships,  hardly  300  feet  from 
shore,  did  not  suffer  at  all  from  these  fevers. 

During  an  investigation  of  latent  malaria  in  natives  living  about  Camp 
Stotsenburg,  in  the  Philippine  Islands,  I  found  that  the  little  barrios  or  villages 
differed  greatly  in  the  amount  of  malarial  infection  present  in  them.  The  per- 
centage of  infected  children  varied  from  as  high  as  60  per  cent,  to  as  low  as  5 
per  cent.,  yet  all  of  the  barrios  were  situated  within  a  radius  of  two  miles. 
Such  a  variation  could  not  occur  were  the  malarial  fevers  transmitted  by  the 
atmosphere.  Not  only  did  the  barrios  vary  in  the  number  of  infections,  but 
certain  portions  of  individual  barrios  were  most  malarious,  while  other  portions 
were  free  from  infection. 

It  has  long  been  known  that  malaria  does  not  develop  in  high  regions 
in  some  instances,  even  though  such  regions  be  surrounded  by  the  most  highly 
infected  territory;  in  other  words,  the  infection  of  malaria  does  not  travel  far 
in  a  vertical  direction.  For  centuries  the  inhabitants  of  the  Pontine  marshes 
have  protected  themselves  from  malaria  by  sleeping  in  elevated  shelters,  and 
the  inhabitants  of  all  malarial  regions  recognize  that  the  upper  stories  of  houses 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  8l 

are  less  apt  to  be  infected  with  these  fevers  than  are  the  lower.  Toniassi- 
Crudeli  found  that  at  Girgento,  the  custodians  of  the  temples  suffer  greatly 
from  malaria,  while  people  sleeping  in  houses  a  short  distance  away,  but  upon 
higher  ground,  do  not  suffer  at  all;  Celli  instances  the  case  of  the  workers  in  the 
marshes  at  the  foot  of  the  Lepini  Mountains,  who  at  night  go  up  into  the  foot- 
hills to  sleep  and  who  thus  escape  malarial  infection.  The  town  of  Norma 
is  built  upon  the  summit  of  an  almost  perpendicular  mass  of  rock,  343  meters 
high,  and  the  inhabitants  are  free  from  malaria.  According  to  Celli,  the 
town  of  Ninfa,  situated  at  the  foot  of  the  rock  upon  which  Norma  is  built, 
and  which  was  once  a  flourishing  Papal  seat,  now  consists  of  ruins,  the  only 
inhabited  house  being  a  mill,  where  malaria  is  so  severe  that  the  workers  have 
to  be  changed  every  week  during  the  malarial  season.  While,  as  a  rule,  malaria 
is  not  met  with  upon  highlands,  there  are  many  exceptions,  and  in  the  Philip- 
pines one  of  the  worst  malarial  foci  in  all  the  islands  is  situated  in  the  foot-hills 
of  the  Zambales  Mountains.  Height  is  only  protective  when  conditions  are 
present  preventing  the  development  of  Anophelinae,  and  the  mere  fact  that  a 
country  is  elevated  should  not  be  considered  as  proving  that  it  is  free  from 
malaria. 

It  would  appear  that  the  most  convincing  argument  against  the  transmission 
of  malaria  by  the  air  is  the  fact  that  the  disease  is  not  conveyed  by  winds,  for 
it  is  impossible  to  believe  that  if  the  malarial  germ  were  present  in  the  air  it 
would  not  be  carried  by  the  wind.  The  malarial  fevers  are  strictly  local 
infections,  being  confined  within  certain  well-defined  limits,  even  in  infected 
localities. 

Transmission  by  Water. — The  believers  in  the  theory  that  water  is 
capable  of  transmitting  malaria  have  instanced  numerous  occurrences  which 
appear  to  support  their  contention.  The  oft-quoted  Argo  incident,  used  so 
often  as  an  almost  impregnable  argument  in  favor  of  such  a  mode  of  trans- 
mission, is  of  little  scientific  value  in  the  light  of  our  present  knowledge.  Boudin 
reported  this  epidemic,  which  occurred  upon  the  French  transport  "Argo," 
in  1834.  In  July  of  that  year,  three  French  transports  sailed  from  Bona, 
Algiers,  bound  for  Marseilles,  and  loaded  with  French  soldiers.  While  upon 
two  of  the  transports  the  troops  continued  in  good  health,  upon  one,  the  ' '  Argo, 
there  occurred  a  severe  epidemic  of  what  was  regarded  as  malarial  fever, 
thirteen  of  the  crew  dying,  while  98  were  admitted  to  the  hospital  when  the 
ship  reached  Marseilles.  The  cause  of  the  epimedic  was  supposed  to  be  a 
number  of  barrels  of  water  from  a  swamp,  shipped  at  Bona,  where  malaria  was 
prevalent.  A  review  of  the  facts  in  this  celebrated  case  show  that  it  is  almost 
impossible  that  any  of  the  patients  suffered  from  malaria,  for  the  incubation 
period  was  shorter  than  has  ever  been  observed;  every  man  of  the  120  consti- 
tuting the  crew  was  affected;  in  every  case  the  symptoms  were  described  as  per- 
nicious in  character,  and  in  no  case  was  there  a  recurrence  of  the  disease.  It  is 
very  evident  that  these  men  suffered  from  some  form  of  acute  poisoning,  perhaps 
due  to  the  swamp  water,  but  more  probably  due  to  some  article  of  food.  The 
6 


82 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 


simultaneous  occurrence  of  the  disease  in  every  one  of  a  crew  of  120  men  is 
positive  proof  that  it  could  not  have  been  due  to  the  malarial  plasmodia. 

Other  similar  epidemics  have  been  reported  as  occurring  upon  ships,  but 
none  of  them  are  of  any  scientific  value  as  proof  of  the  transmission  of  malaria 
by  means  of  water. 

As  an  instance  of  the  erroneous  conclusions  that  may  be  drawn  from  appear- 
ances, the  following  description  of  an  epidemic  of  malaria,  noted  by  Davidson, 
is  of  interest:  The  troops  stationed  at  Tilbury  Fort  suffered  greatly  from 
malaria,  while  those  residing  about  the  railway  station,  and  the  coast  guards, 
were  in  excellent  health.  The  water-supply  of  the  fort  came  from  a  neighboring 
swamp,  while  that  of  the  station  and  of  the  coast  guards  was  from  a  spring. 
While  the  water  tanks  at  the  fort  were  being  repaired,  the  soldiers  also  used 
the  spring  water,  and  the  malaria  disappeared.  Hence  the  inference  was 
clear  that  the  swamp  water  produced  the  malaria,  and  at  that  time  such  an 
inference  was  justifiable,  but  how  easily,  at  the  present  time,  the  disappearance 
of  malarial  fever  at  this  station  can  be  explained.  The  tanks  which  were 
uncovered  served  as  breeding  places  for  mosquitoes;  while  the  tanks  were 
being  repaired  the  mosquitoes  could  not  breed  and  malaria  disappeared. 

Numerous  investigators  have  endeavored  to  produce  malaria  in  man  by 
the  use  of  water  from  malarial  districts,  but  all  such  experiments  have  ended 
in  failure.  Celli  was  the  pioneer  in  this  line  of  research  and  his  experiments 
are  given  in  the  following  table: 


Method 

No.    experi- 
mented  on 

Duration  of  ex- 
periment 

Water  from 

Result. 

By  ingestion. 

6 

8-15  days. 

Pontine  marshes. 

Negative. 

12 

12-21  days. 

Sicily. 

Negative 

3° 

5-30  days. 

Tuscan  Ma- 
remma. 

Negative. 

25 

6-24  days. 

Vallomonica. 

Negative. 

By  inhala- 

16 

2-1  5  days. 

Pontine  marshes. 

Negative. 

tion. 

Twice  a  day. 
20-30    min- 
utes. 

By  entero- 

5 

2-14  days. 

Pontine  marshes. 

Negative. 

clysm. 

THE    ETIOLOGY    OF    THE    MALARIAL    LEVERS.  83 

Some  of  the  above  experiments  were  undertaken  by  Zeri  at  Celli's  sug- 
gestion, and  all  of  them  were  negative  so  far  as  the  production  of  malaria  was 
concerned.  Since  the  discovery  of  the  transmission  of  malaria  by  the  mosquito, 
it  has  been  suggested  that  perhaps  the  plasmodia,  after  passing  through  their 
life  cycle  in  the  mosquito,  may  exist  in  water  in  the  form  of  resistant  spores, 
or  that  the  eggs  of  the  mosquito,  when  ingested  in  water,  may  be  capable  of 
conveying  the  infection.  Nunmerous  observers  have  shown,  however,  that 
the  malarial  plasmodia  are  not  present  in  the  eggs  of  infected  mosquitoes,  and 
no  form  of  the  plasmodia  has  ever  been  found  in  the  water  of  malarious  regions. 
Laveran,  and  later  Manson,  suggested  that  water  might  become  infected 
by  the  dead  bodies  of  infected  mosquitoes,  and  Ross  undertook  to  prove  this 
hypothesis.  He  gave  a  native  water  containing  the  dead  bodies  of  mosquitoes 
infected  with  malarial  plasmodia,  the  ingestion  of  which  was  followed  in 
eleven  days  by  an  attack  of  fever,  with  plasmodia  in  the  blood.  The  ex- 
periment was  of  no  positive  value  as  it  was  carried  out  in  a  malarial  region, 
and,  although  repeated  in  many  individuals,  was  never  again  successful. 

Transmission  by  Inoculation  of  Malarial  Blood. — While  the  direct 
inoculation  of  the  blood  of  a  patient  suffering  from  malaria  into  a  healthy 
individual  probably  occurs  very  rarely  in  nature,  it  is  well  known  that  the 
malarial  fevers  may  be  easily  transmitted  in  this  way.  These  fevers  have  been 
successfully  reproduced  in  this  way  by  Gerhardt,  Mariotti,  Marchiafava, 
Celli,  Bignami,  Bastianelli,  Baccelli,  Sacharoff,  Elting,  and  many  others.  It 
has  invariably  been  found  that  the  species  of  plasmodium  in  the  blood  injected 
is  found  again  in  the  blood  of  the  individual  so  infected,  and  is  followed  by  the 
clinical  symptoms  of  that  type  of  fever  usually  produced  by  the  species  of 
plasmodium  experimented  with.  For  instance,  the  subcutaneous  inoculation 
of  blood  from  a  person  suffering  from  a  benign  tertian  infection  into  a  healthy 
individual  is  followed  by  the  occurrence  of  tertian  fever  in  that  individual, 
and  the  appearance  in  his  blood  of  Plasmodium  vivax.  This  fact  proves 
conclusively  that  there  are  different  species  of  malarial  plasmodia,  each  capable, 
and  capable  only,  of  producing  the  characteristic  clinical  symptoms  with  which 
it  is  always  associated. 

Gerhardt,  in  1884,  was  the  first  to  successfully  inoculate  malarial  fever  in 
man,  and  his  work  was  soon  confirmed  by  that  of  others.  Antolisei  and 
Angelini  produced  typical  tertian  fever  in  two  cases  by  the  inoculation  of  the 
blood  of  a  patient  suffering  from  this  form  of  fever,  while  Gualdi  and  Antolisei 
produced  quartan  fever  in  the  same  way;  in  1889  the  same  observers  inoculated 
a  man  with  blood  containing  hyaline  and  crescentic  forms  of  the  aestivo- 
autumnal  plasmodia,  and  on  the  ninth  day  afterward  typical  "ring"  forms  of 
the  organism  were  found  in  the  blood,  and  an  irregular  fever  developed. 
Crescentic  forms  appeared  upon  the  tenth  day  after  the  onset  of  the  fever. 

Calandrucio  inoculated  himself  from  a  case  of  quartan  malaria,  produced 
by  inoculation,  and  in  18  days  developed  a  typical  quartan  fever,  the  plasmodia 
being  found  in  his  blood.     Bein  produced  tertian  fever,  with  characteristi ; 


84  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

paroxysms,  in  four  cases,  by  the  inoculation  of  blood  containing  the  tertian 
Plasmodium  withdrawn  by  leeches,  and  in  one  case  produced  a  tertian  attack 
by  the  inoculation  of  blood  from  an  experimental  case  of  tertian  malaria. 

An  experiment  of  Di  Mattei  is  of  interest,  both  because  two  types  of  fever 
were  produced  at  different  times  in  the  same  case,  and  because  he  claimed  to 
have  produced  an  aestivo-autumnal  fever  by  the  inoculation  of  blood  containing 
only  the  crescentic  form  of  the  plasmodium.  The  patient  experimented  upon 
had  suffered  from  quartan  malaria  for  some  time  previously,  but  had  recovered. 
He  was  inoculated  with  blood  from  a  case  of  irregular  fever,  which  showed 
only  crescents  at  the  time  of  inoculation.  About  eight  days  after  inoculation 
the  patient's  blood  showed  non-pigmented,  hyalin  parasites.  No  fever  occurred 
until  sixteen  days  after  inoculation,  and  it  was  nine  days  after  the  onset  of 
the  fever  before  crescents  were  found  in  the  blood,  or  25  days  after  inoculation. 
Di  Mattei  followed  this  experiment  by  injecting  into  the  same  patient  blood 
from  a  case  of  quartan  malaria,  and  in  fifteen  days  quartan  fever  appeared, 
and  quartan  plasmodia  were  present  in  large  numbers  in  the  blood.  While  Di 
Mattei  considered  that  the  blood  inoculated  contained  only  crescents,  it  is 
evident,  from  what  we  know  of  the  development  of  the  malarial  plasmodia, 
that  he  must  have  inoculated  asexual  forms  of  the  organism. 

Sacharoff  produced  aestivo-autumnal  malaria  in  himself  by  the  inocula- 
tion of  infected  blood  which  had  been  removed  from  the  body  for  four  days. 
He  allowed  leeches  to  suck  the  blood  of  a  case  of  pernicious  malaria  whose 
blood  contained  immense  numbers  of  hyalin,  non-pigmented  "ring"  forms  of 
the  aestivo-autumnal  plasmodia.  The  leeches  were  kept  upon  ice  for  four  days, 
at  the  end  of  which  time  he  injected  1  c.c.  of  blood  from  one  of  them  into  his 
arm.  At  the  end  of  12  days  he  had  a  malarial  paroxysm,  accompanied  by  a 
chill,  which  was  repeated  upon  the  following  day,  and  an  examination  of  his 
blood  demonstrated  the  presence  of  numerous  typical  "ring"  forms  of  the 
aestivo-autumnal  plasmodia. 

From  the  foregoing  it  is  evident  that  the  malarial  fevers  may  be  inoculated 
from  man  to  man  by  the  injection  of  infected  blood  and  that  the  species  of 
plasmodium  inoculated  is  always  found  in  the  blood  of  the  infected  individual. 

Transmission  by  the  Mosquito. — The  one  method  of  the  transmission 
of  malaria  which  has  been  confirmed  by  abundant  experimental  evidence,  and 
which  to-day  is  accepted  by  all  authorities,  is  that  by  the  bite  of  infected 
mosquitoes.  I  believe  that  this  is  the  only  way  in  which  these  fevers  are 
naturally  transmitted,  and  certainly  it  is  the  only  way  which  has  been  actually 
proven  and  which  is,  therefore,  worthy  of  our  belief.  In  a  most  convincing 
manner  Marchiafava  and  Bignami  refute  the  arguments  of  the  air  and  water 
theorists,  and  sum  up  in  favor  of  the  transmission  of  the  disease  by  the  mosquito 
as  follows: 

"Thus,  admitting  that  malaria  in  man  is  the  result  of  inoculation  by  mos- 
quitoes, it  is  not  difficult  to  explain  why  it  is  practically  not  carried  by  the  wind; 
it  is  also  easy  to  understand  why  the  danger  of  acquiring  malaria  is  greatest  in 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  85 

the  evening  and  the  night.  We  see  at  once  why  the  infection  does  not  rise  far 
above  the  ground;  we  comprehend  readily  the  danger  of  sleeping  in  malarious 
districts;  and  finally  this  theory  explains  perfectly  the  well-known  prophylactic 
efficiency  of  mosquito-nets  in  regions  where  malaria  prevails.  Also  this  agrees 
with  what  we  know  of  the  habits  of  mosquitoes  in  malarious  countries,  which 
sting  especially  at  evening  and  during  the  night,  do  not  fly  far  from  marshes,  or 
places  where  the  proper  conditions  of  their  existence  prevail,  are  in  hiding 
during  the  day  out  of  the  way  of  the  winds,  are  most  numerous  in  places  where 
malaria  prevails,  disappear  from  places  where  works  of  sanitation  have  removed 
the  conditions  necessary  to  their  existence,  do  not  fly  to  any  great  height  above 
the  ground,"  and  many  other  arguments. 

Nuttall,  in  an  elaborate  review  of  the  evidence  in  favor  of  the  transmission 
of  malaria  by  the  mosquito,  mentions  the  following  facts,  which  I  have  tabulated 
below: 

1.  The  Malarial  Season. 

A.  Corresponds  to  a  period  of  warmth  and  moisture,  conditions  most 
favorable  for  the  development  of  mosquitoes. 

B.  Develops  after  the  first  rains,  which  form  pools  in  which  mosquitoes 
may  develop. 

C.  Malaria  often  ceases  after  excessive  rains,  when  such  pools  are  flooded 
and  washed  out,  thus  destroying  the  mosquito  larvae. 

D.  Malaria  is  most  prevalent  in  wet  years,  when  mosquitoes  are  most 
numerous. 

2.  The  Malarial  Country. 

A.  Malaria  is  most  common  in  low,  moist  countries,  swamps,  jungles,  low 
sea-boards,  river  deltas  and  valleys,  and  in  such  places  mosquitoes  most  abound. 

B.  Malaria  becomes  more  common  as  the  equator  is  approached,  which  is 
also  true  of  the  abundance  of  mosquitoes. 

3.  Conditions  Affording  Protection  from  Malaria  and  Mosquitoes. 

A.  Protection  of  the  body,  such  as  is  afforded  by  closing  the  windows  and 
doors  at  night  and  using  mosquito-nets,  gauze,  veils,  curtains,  etc.,  has  long 
been  recognized  by  the  inhabitants  of  malarial  countries  as  protective  against 
the  malarial  fevers. 

B.  Thickly  built  houses  exclude  malaria.  Malarial  fever  seldom  penetrates 
far  into  cities,  as  mosquitoes  are  stopped  by  walls,  hedges,  etc.,  and  are  at- 
tracted by  the  lights  in  the  suburbs. 

C.  Intervening  woods  and  expanses  of  water  protect  from  malaria,  the 
woods  by  obstructing  the  passage  of  the  mosquitoes,  acting  as  a  sort  of  screen; 
the  bodies  of  water  because  the  mosquitoes  perish  in  them  or  do  not  attempt  to 
cross  them,  as  these  insects  are  incapable  of  prolonged  flight. 

D.  Cultivation  of  the  soil:  Malaria  is  often  prevented  by  cultivation  of  the 
soil,  due  to  the  fact  that  this  destroys  the  stagnant  pools  and  swamps,  or  "mos- 
quito nurseries." 

E.  Flooding  the  land  will  prevent  malaria  by  destroying  the  breeding 
places  of  the  mosquitoes. 


86  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

F.  Avoidance  of  sleeping  out-of-doors  at  night  or  exposure  after  sunset: 
The  mosquitoes  bite  mostly  at  night,  and  when  asleep  the  individual  is  bitten 
frequently,  thus  increasing  the  chances  of  infection. 

G.  Use  of  fires:  Fires  indoors  or  out  protect  against  malaria  because  the 
mosquitoes  are  attracted  by  them,  and  fly  into  them  and  perish  before  reaching 
the  person. 

H.  Immunity  of  persons  working  in  sulphur  mines  in  malarious  regions 
due  to  the  fact  that  mosquitoes  are  driven  away  by  the  smell  of  sulphur. 

4.  Influence  of  Occupation. — The  more  exposed  a  person  is  to  the  night 
air  in  malarial  regions,  by  reason  of  his  occupation,  the  more  liable  is  he  to  con- 
tract malaria,  as  he  is  thus  exposed  to  the  bites  of  mosquitoes. 

5.  Effect  of  Turning  Up  the  Soil. — Malaria  often  follows  the  turning  up 
of  the  soil,  as  in  extensive  excavation  works,  and  this  is  due  to  the  fact  that 
the  inequalities  of  the  excavated  land  gives  rise  to  small  pools,  which  form 
suitable  breeding  places  for  mosquitoes. 

6.  Elevation  and  Malaria. — Malaria  is  most  dangerous  near  the  ground, 
and  people  living  in  the  upper  stories  of  houses  suffer  much  less  severely  from 
these  fevers  than  those  living  upon  the  ground  floor.  Mosquitoes  fly  low,  and 
the  nearer  the  ground  one  is  the  more  apt  is  he  to  be  bitten. 

7  The  Coincidence  of  Malaria  and  Mosquitoes. — Wherever  there  is 
malaria  there  we  may  be  sure  of  finding  mosquitoes  belonging  to  the 
Anophelinae. 

It  is  evident  from  the  above  that  the  epidemiological  data  concerning  the 
malarial  fevers  present  strong  presumptive  evidence  in  favor  of  the  trans- 
mission of  the  disease  by  the  mosquito,  but  we  do  not  have  to  deqend  upon 
this  evidence  alone,  for  we  are  now  possessed  of  a  mass  of  experimental  evidence 
which  proves  beyond  all  doubt  that  the  malarial  fevers  are  inoculated  into  man 
by  the  mosquito.  To  the  brilliant  work  of  Manson,  Ross,  Bignami,  Bastianelli, 
Marchiafava,  and  Grassi  the  world  is  indebted  for  the  elucidation  of  one  of  the 
most  important  of  etiological  questions. 

I  have  already  considered  the  development  of  the  malarial  plasmodia 
within  the  mosquito  and  have  given  a  brief  historical  summary  of  the  growth 
of  our  knowledge  concerning  this  question;  here  it  is  my  purpose  to  give 
in  detail  the  most  interesting  of  the  experimental  evidence  proving  that  the 
mosquito  transmits  the  malarial  fevers. 

Bignami  was  the  first  to  succeed  in  producing  malaria  by  the  bites  of 
infected  mosquitoes.  His  patient,  one  Sola,  who  had  been  an  inmate  of  the 
Santo  Spirito  Hospital  for  six  years,  suffering  from  a  nervous  disorder,  but 
who  had  never  had  malaria,  offered  himself  voluntarily  as  a  subject  for  the 
experiment.  The  mosquitoes  used  were  from  Maccarese,  an  intensely  malarious 
locality,  and  the  following  is  Bignami's  record  of  the  experiment: 

"Sola  slept  in  the  room  in  which  the  infected  mosquitoes  had  been  liberated 
from  September  26  to  the  end  of  October.  During  the  latter  part  of  October 
the  patient  complained  of  malaise  and  headache.      On  the  afternoon  of  October 


THE    ETIOLOGY    OF    THE    MALARIAL    LEVERS.  87 

3 1,  he  had  a  slight  elevation  of  temperature  to  37. 2°  C.  (990  F.).  On  November  1, 
at  about  3  p.  m.,  he  was  taken  with  a  severe  chill  which  lasted  until  5  o'clock, 
the  temperature  rising  rapidly  to  above  390  C.  (102.2  F.).  Between  9  and  10 
o'clock  a  feeling  of  cold  was  again  experienced.  The  fever  continued  all  night, 
falling  in  the  early  morning  (November  2)  to  38. 2°  C.  (100. 8°  F.),  and  rising 
again  that  evening  to  39. 30  C.  (102. 70  F.).  The  patient  was  restless  and  com- 
plained of  severe  headache,  but  there  were  no  grave  symptoms.  In  the  night, 
about  11  o'clock,  he  had  another  chill  of  short  duration.  During  this  night  the 
temperature  remained  above  390  C.  (102.20  F.),  and  on  the  morning  of  November 
3  rose  above  40. 40  C.  (104. 7°F.),  the  patient  being  very  restless  and  complaining 
of  much  suffering.      The  fever  broke  in  the  afternoon  with  a  gentle  perspiration. 

"At  quarter  after  five  in  the  afternoon  a  hypodermic  injection  of  one  gram 
of  quinine  was  given  and  repeated  at  night.  The  fever  fell,  and  at  8  a.  m.,  on 
November  4,  the  temperature  was  36.70  C.  (980  F.).  The  administration  of 
quinine  was  continued  during  the  following  days,  the  patient  continuing  to  have 
slight  elevations  of  temperature  which  did  not  reach  380  C.  (100. 40  F.)  except 
once,  on  November  6.  From  November  7  onward  the  patient  was  entirely 
without  fever,  and  rapidly  regained  his  appetite  and  strength. 

"An  examination  of  the  blood  made  with  the  greatest  care  on  November  2 
gave  negative  results,  no  malarial  parasites  being  found.  On  the  morning  of 
November  3  a  few  young  annular  parasites,  motile  and  discoid,  without  pigment, 
and  presenting  the  characteristic  appearance  of  the  parasites  of  aestivo-autumnal 
fever  were  found.  These  forms  increased  in  number  during  the  day,  and  were 
quite  numerous  during  the  afternoon  hours.  In  some  there  was  a  beginning 
pigmentation  at  the  border  consisting  of  very  fine  granules  of  pigment. 

"  We  see,  therefore,  that  there  was  produced  experimentally  in  Sola  a  grave 
malarial  fever  with  a  temperature  curve  such  as  is  frequently  seen  in  a  primary 
aestivo-autumnal  infection.  The  fever  began  briskly,  continued  with  slight 
remissions  from  November  1  to  3,  and  began  to  fall  on  the  evening  of  the  latter 
day  when  the  specific  remedy  was  administered.  The  parasites  found  in  the 
blood  belonged  to  the  aestivo-autumnal  species. 

"This  is  perhaps  the  first  time  that,  in  the  primary  aestival  infection 
acquired  in  the  natural  way,  examinations  of  the  blood  have  been  made  from  the 
beginning  of  the  fever.  We  find  that  after  forty  hours  the  parasites  begin  to 
be  found,  at  first  in  small  numbers,  but  rapidly  becoming  more  and  more  numer- 
ous. 

"According  to  the  opinion  of  all  who  followed  this  experiment,  it  was  con- 
ducted in  such  a  way  as  to  silence  all  objections.  Sola  is  a  robust  individual, 
notwithstanding  his  nervous  malady,  who  has  never  in  his  life  had  malarial  fever, 
and  who  has  not  been  outside  of  the  Santo  Spirito  Hospital  for  six  years.  The 
room  where  the  experiment  was  conducted  was  an  annex  of  the  San  Carlo  ward, 
in  which,  within  the  memory  of  the  hospital  physicians,  there  has  never  been  an 
autochthonous  case  of  malarial  fever,  nor  has  there  ever  been  any  malaria  in  the 
neighboring  houses. 

"  Now  in  a  room  in  the  San  Carlo  ward  of  the  Santo  Spirito  Hospital  (Rome) 
Sola  acquired  a  malarial  infection  produced  by  aestivo-autumnal  parasites,  with 
a  well-marked  fever  and  symptoms  so  grave  as  to  call  for  the  prompt  adminis- 
tration of  quinine.  The  fever,  indeed,  was  exactly  such  a  one  as  is  ordinarily 
caught  by  laborers  in  the  Roman  Campagne  in  the  summer  and  autumn  months, 
a  fever  beginning  with  the  typical  curve  of  the  aestivo-tertian  or  sometimes 
with  a  continued  curve.  This  identical  fever,  such  as  prevails  at  Maccarese, 
was  taken  by  Sola  in  a  place  where  there  was  of  Maccarese  neither  the  water 
nor  the  soil  nor  the  air,  but  the  mosquitoes  alone.      We  are  then  forced  to  the 


88  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

conclusion  that  the  fever  was  acquired  by  inoculation  by  the  mosquitoes.  While 
in  this  case  there  could  be  no  doubt  that  the  mosquitoes  were  responsible  for 
the  fever,  it  was  not  definitely  determined  just  what  species  of  mosquitoes 
was  concerned,  as  there  were  three  different  species  liberated  in  the  room. 
After  this  experiment.  Grassi,  Bastianelii,  and  Bignami  worked  with  A.  maculi- 
pennis,  and  never  failed  to  produce  the  disease  when  they  were  used.  The 
following,  a  successful  experiment  performed  by  Bastianelii  and  Bignami,  and 
quoted  in  their  own  words,  is  of  interest  in  many  ways: 

"A  patient  suffering  from  a  relapsing  aestivo-autumnal  infection,  in  whose 
blood  were  many  crescents  and  round  and  flagellated  bodies,  slept,  from 
December  10  to  18,  in  a  room  in  which  had  been  set  free  about  50  individuals 
of  .4.  maculapennis,  brought  from  Maccarese.  The  temperature  of  the  room 
was  maintained  at  from  18°  to  220  C.  (64. 40  to  71. 6°  F.).  Most  of  the  mos- 
quitoes stung  the  patient,  and  became  infected  with  crescent  bodies,  and  sub- 
sequent examinations  showed  in  the  middle  intestine  the  characteristic  forms  in 
process  of  development.  But  it  was  also  observed  that  the  mosquitoes  remain- 
ing in  the  room  at  the  given  temperature  during  the  last  days  of  December  did 
not  have  in  the  intestines  mature  sporozoa  with  sporozoites,  but  only  the  growing 
forms.  Evidently  at  a  temperature  of  from  180  to  220  C.  the  life  cycle  of  the 
parasite  is  completed  very  slowly.  But  these  same  mosquitoes,  confined  for  a 
few  days  in  an  incubator  at  a  temperature  of  300  C.  (86°  F.),  were  found  to 
contain  forms  of  a  later  development.  There  were  noted,  enclosed  in  the  intes- 
tines, typical  capsules  filled  with  sporozoites,  and  also  broken  and  empty  capsules, 
and  in  the  salivary  glands  were  numerous  sporozoites. 

"When  this  fact  was  noted,  three  mosquitoes  of  this  group  were  kept  in  an 
incubator  at  300  C.  for  two  days,  and  on  January  2  they  were  made  to  sting  a 
new  subject,  A.  R. ,  who  lent  himself  knowingly  and  willingly  to  the  experi- 
ment. It  is  needless  to  say  that  this  man  had  never  had  malaria.  On  January 
5  two  of  the  same  mosquitoes  were  made  to  sting  the  same  person  again,  who 
then  had  been  stung  in  all  five  times  by  three  specimens  of  A.  maculapennis . 

"After  this  part  of  the  experiment,  the  three  mosquitoes  were  dissected, 
and  examined  under  the  microscope,  with  the  following  results:  A.  maculi- 
pennis.  No  1.  In  the  intestines  were  found  many  capsules  with  sporozoites,  and 
some  capsules  which  had  been  ruptured  and  completely  emptied  of  their  contents. 
In  the  salivary  glands  were  found  two  infected  tubules;  in  one  the  cells  were 
swollen,  of  ovoid  form,  and  filled  with  granules  of  uniform  size.  When  pressure 
was  made  on  the  preparation  there  issued  a  very  large  number  of  sporozoites  of 
typical  form,  uniform  in  appearance,  and  all  of  equal  length;  in  the  other  tubule 
were  also  seen  cells,  containing  filiform  sporozoites  of  characteristic  appearance. 

"A.  maculipennis.  No.  2.  In  the  intestine  were  very  numerous  capsules, 
some  still  whole  and  filled  with  sporozoites,  others  ruptured  and  shrunken,  and 
containing  a  granular  residuum  of  a  pale  yellow  color.  In  some  of  these  ruptured 
capsules  were  seen  brown  bodies  of  various  size  and  shape,  some  elongated,  others 
short  and  deformed.  In  the  salivary  glands  all  the  tubules  were  infected  except 
one  or  two.  In  them  were  seen  cells  containing  typical  sporozoites,  cells  filled 
with  granules  similar  to  those  described  in  A.  maculipennis,  No.  1,  and  cells 
filled  with  round  hyaline  bodies  of  variable  size.  In  addition  there  were  also 
found  typical  filiform  sporozoites  along  the  excretory  ducts  of  the  gland. 

"A.  maculipennis.  No.  3.  The  intestine  was  filled  with  mature  sporozoa. 
Many  capsules  were  broken  and  shrunken,  and  contained  a  pale  yellow  detritus; 
others  contained  a  large  central  body  of  granular  aspect,  surrounded  by  a  hyaline 
halo  and  without  any  recognizable  structure.  These  were  possibly  mature 
sporozoa  in  process  of  degeneration.    The  salivary  glands  were  not  found  infected. 


THE  ETIOLOGY  OF  THE  MALARIAL  FEVERS.  89 

"From  the  results  of  these  examinations  we  may  conclude  that  of  the  three 
specimens  of  A.  macnlipennis  employed,  only  two  had  inoculated  the  patient 
with  malaria. 

"On  the  evening  of  January  10,  the  patient  had  a  sense  of  heat  and  a  head- 
ache, but  the  temperature  was  normal.  On  January  n,  12,  and  13,  there  was 
no  fever  and  the  patient  felt  well.  On  January  14,  that  is,  after  from  9  to  12 
days'  incubation,  there  was  no  fever  until  8  o'clock  in  the  morning,  but  then  the 
temperature  began  to  rise  rapidly  and  reached  39. 50  C.  (103. i°  F.)  at  noon.  From 
this  time  the  fever  remained  continuous  up  to  January  18.  The  temperature 
fell  to  normal  in  the  morning  of  the  eighteenth.  (Two  grams  of  quinine  were  given 
hypodermically  on  the  sixteenth,  and  repeated  on  the  seventeenth,  and  re- 
covery was  complete  and  rapid. 

"On  examination  of  the  blood  on  the  morning  of  January  16,  there  were 
found  scanty  aestivo-autumnal  parasites  with  very  fine  pigment  granules  at  the 
periphery.  There  were  found  also  plasmodia  without  pigment  and  with 
granules  in  normal  red  blood-corpuscles  and  in  brassy  bodies.  The  parasites 
disappeared  after  the  exhibition  of  quinine  on  January  17.  Thus  the  infection 
was  rapidly  cut  short  and  no  crescent  bodies  were  seen. 

"We  have  in  this  case  a  typical  example  of  aestivo-autumnal  infection,  be- 
ginning with  a  continued  fever,  as  is  usual  with  this  group  of  malarial  infec- 
tions. The  course  of  the  disease  was  in  every  respect  identical  with  that  in  the 
first  case  of  malarial  fever  experimentally  produced  by  the  stings  of  mosquitoes 
(the  Sola  case,  described  by   Bignami)." 

From  the  above  it  will  be  seen  that  in  this  case  the  disease  was  caused  by 
the  bites  of  only  two  insects,  and  this  is  not  surprising  when  one  considers  the 
immense  number  of  sporozoites  in  the  infected  salivary  glands  of  a  single 
mosquito.  There  i  no  reason  to  doubt  but  that  one  mosquito  may  infect  a 
large  number  of  individuals. 

One  of  the  most  striking  confirmations  of  the  truth  of  the  mosquito  theory 
of  the  transmission  of  the  malarial  fevers  is  found  in  the  experiments  of  Sambon 
and  Low.  These  investigators  spent  an  entire  summer  at  Ostia,  a  most 
malarious  region  in  the  Roman  Campagna,  residing  in  a  mosquito-proof  hut. 
During  the  day,  the  time  was  spent  mostly  out  of  doors,  but  early  in  the  evening 
the  observers  retired  to  their  hut  and  there  spent  the  night.  Neither  investigator 
developed  malaria,  although  many  individuals,  residing  in  the  same  locality, 
without  protection  from  mosquitoes,  suffered  severely  from  the  disease.  Ostia 
is  so  malarious  that  it  was  formerly  said  that  to  spend  one  night  at  that  place 
would  result  in  a  malarial  paroxysm,  and  this  was  proven  recently  when  of 
sixteen  police  officers  who  spent  one  night  at  Ostia,  all  developed  malaria 
within  two  weeks;  yet  Sambon  and  Low  lived  through  an  entire  summer  at 
this  place  and  did  not  suffer  from  malaria,  because  they  spent  the  nights  in  a 
mosquito-proof  hut.  As  showing  the  manner  of  life  of  the  laborers  in  the 
Roman  Campagna  and  how  severely  they  suffer  from  malaria,  the  following 
quotation  from  an  editorial  in  the  British  Medical  Journal  of  December  8, 
1900,  describing  the  experiments  at  Ostia  is  of  interest: 

"Ostia,  like  all  other  malarious  districts  in  the  Roman  Campagna,  has  no 
indigenous  population.      The  little  wretched  town  of  mean  buildings  gathered 


90  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

round  the  old  mediaeval  castle  is  inhabited  by  a  fluctuating  population,  which 
comes  there  from  all  parts  of  Italy,  but  chiefly  from  the  south.  In  winter  a  large 
number  of  laborers  come  to  plough  the  fields  and  sow  the  corn,  but  they  leave 
before  the  end  of  June.  In  summer  other  workman  come  for  short  periods  to 
harvest  the  corn  and  maize.  The  life  of  these  laborers  is  wretched  in  the  extreme ; 
they  may  well  be  called  'white  slaves. '  They  suffer  fearfully  from  malaria. 
They  were  sometimes  met  returning  bare-footed  to  their  distant  homes,  under 
the  scorching  sun,  delirious  from  fever.  They  often  fall  by  the  roadside,  and 
many  have  died  in  the  ditch  in  sight  of  the  great  gray  cupola. 

"They  work  from  dawn  to  sunset  closely  watched  by  overseers  on  horse- 
back, who  drive  them  like  beasts.  If  they  dare  complain  an  infantry  regiment 
is  called  out  to  keep  them  in  order.  Their  food  is  dry  bread.  Those  who  can 
afford  it  add  a  morsel  of  cheese  or  an  onion  to  the  fare.  They  sleep  in  little  huts 
made  of  boughs  and  straw.  Many  have  no  covering  between  themselves  and 
the  starry  heavens.  The  people  who  gather  reeds  at  the  mouth  of  the  river  live 
in  huts  built  on  piles,  which  look  exactly  like  the  tree  houses  or  pile  dwellings 
of  the  New  Guinea  Papuans." 

Can  any  one  reading  this  description  of  industrial  conditions  in  "sunny 
Italy"  wonder  at  the  terrible  mortality  from  malaria  that  has  ever  been  charac- 
teristic of  that  country. 

In  1900,  Manson,  believing  that  the  experiments  of  the  Italian  investigators, 
while  conclusive  to  the  scientific  world,  were  vitiated  in  the  public  mind  by 
the  fact  that  they  were  performed  in  a  malarial  country,  conceived  the  idea  of 
having  infected  mosquitoes  sent  from  Italy  to  him  in  London  and  using  these 
mosquitoes  to  produce  malaria  in  a  healthy  individual,  in  that  city,  where 
malaria  is  unknown,  unless  it  is  imported  in  the  person  of  an  infected  patient. 
Accordingly,  Sambon  sent  Manson  some  mosquitoes  fed  upon  a  case  of  benign 
tertian  malaria  in  Rome,  and  these  mosquitoes  were  used  in  an  experiment 
upon  Manson's  son,  the  late  Dr.  P.  Thurburn  Manson.  The  experiment  is 
given  in  the  latter's  own  words: 

"I  am  twenty-three  years  of  age,  was  born  in  China,  but  have  lived  in  this 
country  (England)  since  I  was  three;  have  never  been  abroad  since,  nor  in  any 
district  in  this  country  reputed  to  be  malarial.      I  am  healthy. 

"The  first  consignment  of  mosquitoes  arrived  at  the  London  School  of  Trop- 
ical Medicine  on  July  5.  Only  some  half-dozen  had  survived  the  journey. 
They  were  in  a  languid  condition  and  would  not  feed  satisfactorily.  One  may 
have  bitten  me.  By  July  7,  they  were  all  dead.  The  second  consignment  ar- 
rived on  August  29.  They  had  been  infected  in  Rome  on  August  17,  20,  and  23, 
by  being  fed  upon  a  patient  with  a  double  benign  tertian  infection.  The  patient 
was  reported  to  have  had  numerous  parasites,  including  many  gametes  in  his 
blood.  On  arrival  twelve  insects  were  lively  and  healthy  looking.  I  fed  five 
of  them  on  August  29,  three  on  August  31,  one  on  September  2,  and  one  on 
September  4.  They  bit  my  fingers  and  hands  readily.  The  bites  were  followed 
by  a  considerable  amount  of  irritation,  which  persisted  for  two  days. 

"The  third  consignment  arrived  on  September  10.  They  had  been  fed  in 
Rome  on  September  6  and  7  on  a  patient  suffering  from  a  simple  tertian  infection 
but  with  very  few  parasites  in  his  blood.  There  were  some  50  to  60  mosquitoes 
in  good  condition.      Twenty-five  bit  me  on  September  10  and  10  on  September  12. 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  91 

"Up  till  September  13,  I  had  been  perfectly  well.  On  the  morning  of  the 
thirteenth  I  rose  feeling  languid  and  out  of  sorts  with  a  temperature  of  990  F. 
By  midday  I  was  feeling  chilly  and  inclined  to  yawn.  At  4.30  p.  m.  I  went  to 
bed  with  severe  headache,  sensation  of  chilliness,  lassitude,  pains  in  the  back  and 
bones  and  a  temperature  of  101.40  F.  Repeated  examinations  failed  to  discover 
any  malarial  parasites  in  my  blood. 

"September  14. — I  slept  fairly  well,  but  woke  at  3  a.  m.  with  slight  sweating 
and  a  temperature  of  10 1°.  During  the  day  my  temperature  ranged  between 
1010  and  1020.  The  symptoms  of  September  13  were  exaggerated  and  anorexia 
was  complete.  Several  examinations  of  the  blood  were  made  again  with  negative 
results. 

"September  1  5.- — Woke  at  7  a.  m.  feeling  distinctly  better,  with  a  temperature 
of  100. 40.  No  malarial  parasites  were  discovered  on  repeated  examinations  of 
my  blood  by  my  father.  About  2  p.  m.  I  commenced  to  feel  slightly  chilly;  this 
soon  wore  off,  and  I  became  hot  and  restless.  By  4.30  p.  m.  temperature  was 
103. 6°.  It  remained  about  1030  till  9  p.  m.  when  profuse  sweating  set  in.  I  am 
told  there  was  some  delirium. 

"September  16. — I  woke  at  8  a.  m.  feeling  quite  well;  temperature  98. 40.  I 
made  several  blood  examinations  and  found  one  doubtful  half-grown  tertian 
parasite.  In  the  afternoon  and  evening  there  was  a  recurrence  of  fever  (tem- 
perature 102.8,  relieved  by  sweating. 

"September  17. — Again  felt  quite  well  on  waking  after  a  good  night's  sleep; 
temperature  990.  At  10  a.  m.  several  half-grown  parasites,  a  gamate,  and  two 
pigmented  leucocytes  were  discovered  in  the  first  blood  film  examined.  During 
the  day  many  tertian  parasites  were  found.  Their  presence  was  confirmed  by 
my  father  and  others.  About  2  p.  m.  the  sensation  of  chilliness  returned.  Tem- 
perature 101.80.  By  5  p.  m.  temperature  had  reached  1030.  There  was  then 
copious  sweating.  The  edge  of  the  spleen  could  be  felt  on  deep  inspiration,  and 
there  was  a  slight  feeling  of  discomfort  in  the  region  of  that  organ.  Dr.  Fred- 
erick Taylor  and  Mr.  Watson  Cheyne  confirmed  the  presence  of  splenic  enlarge- 
ment. By  9  p.  m.  the  temperature  had  fallen  to  99. 20,  and  I  was  feeling  better. 
Quinine   (10  grains)   was  given. 

"September  18. — Woke  after  a  good  night,  feeling  perfectly  well  (tempera- 
ture 970).  Ten  grains  of  quinine  were  taken  and  subsequently  five  grains  every 
eight  hours.  I  continued  perfectly  well  all  day.  A  few  three-quarters  grown 
tertian  parasites  and  some  gametes  were  found  during  the  forenoon  and  afternoon. 
At  10  p.  m.  the  parasites  had  disappeared,  the  last  being  found  at  5  p.  m. 

"September  19. — No  parasites  discovered.  Temperature  normal.  Feeling 
quite  well.  There  is  no  splenic  enlargement,  and  no  tenderness.  Appetite 
returns. 

"September  25. — In  good  health.  No  recurrence  of  malarial  symptoms. 
A  second  experiment  with  mosquitoes  sent  from  Rome  and  infected  with  the 
benign  tertian  plasmodium  was  performed  upon  another  individual  in  London,  and 
was  successful.  In  both  Dr.  Manson's  case  and  in  the  latter,  relapses  occurred 
and  tertian  plasmodia  were  always  easily  demonstrated  in  the  blood." 

In  1899,  Grassi,  Bignami,  and  Bastianelli  found  that  over  75  per  cent,  of 
Anopheles  caught  in  rooms  occupied  by  malarial  .patients  showed  developmental 
forms  of  the  plasmodia  within  them,  and  they  were  successful  in  infecting  A. 
maculipennis  with  the  quartan  plasmodium. 

The  experiments  given  comprise  but  a  small  portion  of  these  which  demon- 
strate beyond  all  doubt  that  the  malarial  fevers  are  transmitted  from  man  to 


92  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

man  by  the  mosquito,  and  while  it  is  not  yet  proven  that  this  is  the  only  mode  of 
transmission,  it  is  but  reasonable  to  suppose  that  this  is  the  case.  Schaudinn 
claimed  to  have  traced  developmental  forms  of  the  plasmodium  in  the  eggs 
of  mosquitoes  and  thus  considered  that  the  disease  might  be  transmitted  by 
the  adult  insect  to  its  progeny  through  the  eggs  and  larvae,  as  in  the  case  of 
Texas  fever  and  relapsing  fever.  His  researches  have  not  been  confirmed  and 
the  experiments  of  Marchiafava  and  Bignami  would  appear  to  indicate  that 
such  hereditary  transmission  of  the  plasmodia  does  not  occur.  Neither  the 
eggs  or  the  larvae  of  infected  Anopheles  showed  the  presence  of  any  form  of  the 
plasmodia,  nor  were  Anopheles,  born  in  the  laboratory,  the  progeny  of  infected 
insects,  able  to  produce  malaria  in  man,  although  six  individuals  were  thus  ex- 
perimented with.  At  the  present  time  the  only  known  method  of  the  transmis- 
sion of  the  malarial  fevers  is  through  the  bite  of  infected  mosquitoes,  and  the 
plasmodia  are  not  present  in  the  ova  of  these  insects. 

Cultivation  of  Malarial  Plasmodia. — No  one  as  yet  has  been  able  to 
cultivate  the  malarial  plasmodia  in  artificial  media  outside  of  the  human 
body.  Coronado,  a  Spaniard,  is  the  only  investigator  who  has  claimed  to  have 
been  successful  in  the  cultivation  of  the  plasmodia,  but  his  experiments  have 
been  repeated  by  other  observers,  none  of  whom  have  been  able  to  confirm  his 
results.  He  claimed  to  have  cultivated  the  plasmodia  in  unsterilized  water. 
In  tubes  of  such  water  containing  mud  from  the  bottom  of  the  supposedly 
infected  pool,  a  small  amount  of  malarial  blood  was  placed,  and  in  24  hours 
Coronado  claimed  that  cultures  developed,  and  the  entire  life  cycle  of  the 
plasmodia  could  be  followed.  His  description  of  this  life  cycle  is  at  vatiance 
with  that  occurring  either  in  man  or  in  the  mosquito,  and  it  is  evident  that  his 
results  are  erroneous,  and  that  he  observed  some  other  organism  in  the  grossly 
contaminated  water. 

The  plasmodia,  however,  have  been  kept  alive  outside  of  the  human  body 
for  several  days.  Sacharoff  was  the  first  to  be  successful  in  such  experiments, 
finding  that  in  malarial  blood  obtained  by  leeches,  from  the  human  subject,  the 
plasmodia  remained  alive  for  over  a  week,  provided  the  leeches  were  kept  upon 
ice.  No  reproductive  changes  occurred  during  this  time.  He  also  found  that 
the  aestivo-autumnal  plasmodia  remained  actively  amoeboid  for  seven  days, 
and  capable  of  causing  malaria  for  four  days;  under  such  conditions,  the 
benign  tertian  plasmodium  remained  amoeboid  for  only  forty-eight  hours. 
Rosenbach  found  that  the  benign  tertian  plasmodium  remained  alive  in  the 
blood  of  leeches  or  forty-eight  hours,  and  he  considered  that  during  this  time 
growth  occurred,  and  possibly  multiplication. 

Blumer,  experimenting  with  blood  containing  aestivo-autumnal  plasmodia, 
found  that  the  small  hyaline  parasites  continued  present  for  over  a  week  in  the 
leech  if  it  were  kept  upon  ice,  but  he  was  not  able  to  demonstrate  amoeboid 
motion,   nor  could   any  evidence  of  growth   or  reproduction  be  discovered. 

Hamburger  and  Mitchell  have  performed  similar  experiments,  which  are 
described  by  Thayer,  as  follows: 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  93 

"Mr.  Hamburger  took  the  blood  from  a  case  of  aestivo-autumnal  fever  with 
quotidian  paroxysms  at  a  time  when  only  small  amoeboid  and  ring-shaped,  non- 
pigmented  hyalin  bodies  were  present.  During  the  next  several  days  he  was 
able  to  distinguish  a  slight  increase  in  size,  with  the  accumulation,  in  nearly 
every  organism,  of  a  few  small,  motile  pigment  granules.  On  the  eight  day 
the  organisms  were  distinctly  visible,  each  with  a  small  group  of  slightly  motile 
granules  in  the  middle  or  at  some  point  on  the  periphery  of  the  parasite.  Specimens 
stained  on  the  eighth  day  showed  characteristic  ring-shaped  bodies.  The  ex- 
periment of  Hamburger,  which  I  was  able  to  follow,  furnishes  the  first  demon- 
stration of  the  actual  growth  of  the  parasite  and  the  accumulation  of  pigment 
outside  of  the  human  body.  (This  was  written  before  the  discovery  of  the 
development  of  the  plasmodia  within  the  mosquito.) 

"Mr.  Mitchell  placed  a  leech  upon  an  individual  suffering  with  a  combined 
aestivo-autumnal  and  double  tertian  infection.  The  blood  showed  two  groups 
of  active  tertian  organisms  and  a  few  crescentic  and  ovoid  forms.  In  the 
body  of  the  leech  the  tertian  organisms  were  to  be  made  out  for  ten  days.  The 
pigment  was  active  for  four  days,  but  no  amoeboid  movement  was  to  be  made  out 
in  the  parasites.  The  crescentic  and  ovoid  bodies  remained  unchanged;  no 
flagellate  forms  were  observed." 

In  the  light  of  our  present  knowledge  concerning  the  transmission  of  these 
fevers  by  the  mosquito,  it  is  interesting  to  note  that  in  the  leech  the  ere  cents  and 
ovoids  underwent  no  further  development,  and  that  flagellated  parasites  were 
entirely  absent. 

In  view  of  Roger's  successful  efforts  in  the  cultivation  of  Le'shmania- 
donovani  in  citrated  blood,  I  have  endeavored  to  cultivate  the  plasmodia  of 
malaria  in  a  similar  manner,  the  method  pursued  being  as  follows: 

The  patient's  arm  is  corded  above  the  elbow  and  sterilized.  A  large 
superficial  vein  is  selected  and  five  cubic  centimeters  of  blood  is  removed  from 
it  with  a  sterilized  glass  syringe,  and  added  to  tubes  containing  from  i  to  2  c.c. 
of  citrate  solution,  the  tubes  being  then  kept  at  room  temperature,  at  blood 
temperature,  and  at  a  temperature  of  220  C.  I  experimented  in  th's  way  with 
blood  containing  the  gametes  (crescents)  of  the  aestivo-autumnal  plasmodia,  and 
with  blood  containing  tertian  gametes,  but  was  unable  to  observe  any  indica- 
tions of  development  in  the  organisms  beyond  flagellation,  which  occurred  soon 
after  the  blood  was  added  to  the  citrate  solut  on.  The  intracellular  plasmod  a 
underwent  no  developmental  changes,  but  soon  degenerated,  although  some 
could  be  distinguished  in  the  red  corpuscles  as  long  as  three  days  after  remov- 
ing the  blood  from  the  patient.  There  appeared  to  be  no  difference,  as  regards 
appearance,  in  the  organisms  kept  at  room  temperature,  in  the  incubator,  or 
at  220  C. 

Immunity. — There  has  for  years  been  considerable  question  as  to  whether 
immunity  to  the  malarial  fevers  exists  in  individuals  or  races.  There  can  be 
no  doubt  that  both  natural  and  acquired  immunity  to  the  malarial  fevers  is 
possible,  and  that  the  presence  of  immunity  against  these  fevers  is  not  so  very 
uncommon  in  individuals  residing  in  malarial  localities.  Koch  firmly  believes 
that  immunity  to  malaria  exists  because  of  the  common  occurrence  of  sponta- 


94  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

neous  recovery  and  the  freedom  from  the  disease  observed  in  certain  groups 
of  people,  as  the  coast  negroes  of  East  Africa,  and  the  Chinese  coolies  of 
Sumatra.  In  these  people  the  immunity  is  undoubtedly  acquired  during  a 
long  residence  in  malarial  localities. 

In  considering  this  portion  of  our  subject  it  will  be  convenient  to  do  so 
under  the  following  divisions:  Natural  immunity,  absolute  and  relative,  and 
acquired  immunity,  absolute  and  relative. 

Natural  Immunity. — By  natural  immunity  We  understand  an  immunity 
occurring  naturally,  the  individual  never  having  suffered  from  the  disease. 
Natural  mmunity  is  generally  hereditary,  and,  in  most  instances,  is  absolute, 
but  occasionally  is  relative,  the  individual,  under  certain  conditions,  succumbing 
to  infection.  An  absolute  natural  immunity  against  malaria  is  sometimes 
observed  in  individuals  and  families,  but  it  is  never  a  racial  characteristic. 
Maurel  concluded  from  his  exhaustive  studies  upon  racial  immunity  that  no 
human  race  is  immune  from  malaria,  although  many  races  have  an  acquired 
immunity.  A  natural  relative  immunity  is  often  observed  in  the  descendants 
of  the  inhabitants  of  very  malarial  communities,  an  immunity  which  is  protective 
until  unusual  exposure  or  hardship  so  undermines  the  natural  resistant  powers 
that  an  infection  results.  An  absolute  natural  immunity  is  observed  in  rare 
instances,  and  almost  every  writer  upon  malaria  has  given  examples  of  such 
immunity.  Celli  instances  the  case  of  four  individuals,  living  at  Sezze,  in  the 
Pontine  marshes,  a  most  malarious  region,  who  have  resided  there  for  years, 
have  never  taken  any  precautions  against  malaria,  yet  who  have  never  suffered 
from  the  disease.  "They  work  very  laboriously,  have  insufficient  and  bad  food, 
frequently  sleep  on  the  marshes,  in  the  open  air  and  in  such  a  manner  as  to  be 
continually  bitten  by  mosquitoes;  still  they  have  never  had  malaria,  are  very 
healthy,  have  a  rosy  color,  and  their  liver  and  spleen  are  normal  in  size." 

Marchiafava  and  Bignami  note  an  interesting  case  of  natural  absolute 
immunity  in  a  family  residing  in  one  of  the  worst  malarial  portions  of  the 
Roman  Campagna.  The  grandfather,  the  father,  and  the  two  sons,  although 
exposed  continually  to  infected  mosquitoes,  have  never  had  malaria,  although 
almost  every  one  living  in  the  same  place  for  any  length  of  time  develops  the 
disease. 

I  have  observed  a  few  instances  of  natural  immunity  among  American 
soldiers,  both  in  Cuba  and  in  the  Philippine  Islands.  These  men,  although 
living  in  most  malarial  regions  and  taking  no  precautions  against  infection, 
never  suffered  from  the  disease,  while  their  companions,  even  those  who  were 
cautious  regarding  exposure  to  mosquito  bites,  one  by  one  developed  paroxysms 
of  fever  with  the  plasmodia  in  the  blood. 

We  thus  see  that  an  absolute  natural  immunity  is  present  in  some  individuals, 
and  while  it  is  comparatively  rare  yet  I  believe  that  more  extended  observation 
will  demonstrate  that  it  is  much  more  common  than  is  generally  supposed. 
My  experience  with  the  malarial  fevers  as  they  occur  among  our  troops  would 
appear  to  show  that  a  not  inconsiderable  proportion  of  the  men  possess  a  natural 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  95 

immunity  to  these  fevers,  probably  relative  in  character,  in  most  instances,  but 
absolute  in  a  goodly  number.  Natural  immunity  is  never  a  racial  characteristic, 
for  no  race  of  men  is  immune,  as  a  race,  to  the  malarial  fevers. 

Acquired  Immunity. — By  the  term  "acquired  immunity"  we  understand 
an  immunity  acquired  through  an  attack  or  attacks  of  a  disease.  It  is  some- 
what doubtful  if  an  acquired  immunity  against  the  malarial  fevers  is  ever  absolute 
in  character,  although  many  sufferers  from  these  fevers  never  have  more  than 
one  attack.  In  the  vast  majority  of  instances  an  immunity  acquired  against 
malaria  is  relative  in  character,  being  overcome  by  many  factors,  such  as 
exposure,  starvation,  mental  or  physical  strain,  an  unusually  large  amount  of 
the  infective  principle,  or  excessive  changes  in  temperature.  The  immunity 
acquired  by  repeated  attacks  of  malaria  is  always  relative  in  character. 

Long  residence  in  a  malarious  country  will,  undoubtedly,  if  the  individual 
survives  repeated  attacks  of  the  disease,  confer  upon  him  a  relative  immunity 
to  malaria.  In  other  words,  the  malarial  poison  produces  certain  changes  in 
the  human  organism  which  render  it  at  least  partially  immune  to  further  attacks. 
This  immunity,  however,  is  often  gained  at  the  expense  of  the  vitality  of  the 
individual,  and  the  penalty  inflicted  is  a  chronic  malaria  cachexia,  which  mark- 
edly lowers  the  health  of  these  immunes.  The  history  of  acquired  immunity  is 
simply  that  of  repeated  attacks  of  malarial  fever,  each  one  a  little  less  severe 
than  the  preceding,  until  at  last  a  spontaneous  cure  is  effected  which  is 
permanent.  It  should  not  be  forgotten  that  in  many  individuals  supposed  to  be 
immune  to  malaria,  the  immunity  consists  in  the  absence  of  symptoms  only 
for  the  examination  of  the  blood  of  such  individuals  will  often  reveal  malarial 
plasmodia  undergoing  schizogony.  In  these  individuals,  the  condition  present 
might  perhaps  better  be  called  an  increased  tolerance  to  the  plasmodia  rather 
than  an  immunity  in  the  restricted  sense  in  which  the  word  is  often  employed. 
This  subject  will  be  considered  more  fully  in  the  chapter  dealing  with  latent 
and  recurrent  malarial  infections,  as  in  such  instances  the  malarial  infection 
is  really  latent  in  character. 

It  is  a  well  recognized  fact  that  the  inhabitants  of  malarial  countries  are 
often  more  resistant  to  the  infection  than  are  new-comers,  and  in  most  instances 
this  immunity,  which  is  relative,  has  been  acquired  through  repeated  attacks 
of  the  disease.  The  black  races  in  some  portions  of  Africa,  although  not 
naturally  immune  to  malaria,  enjoy  a  relative  immunity,  and  even  when  they 
contract  malaria  suffer  much  less  severely  from  it  than  does  the  European. 
Plehn  has  demonstrated  that  the  Kamerun  negroes  rarely  have  malarial  fever, 
and  generally  recover  spontaneously;  whereas  Europeans  suffer  very  severely 
in  the  same  locality.  The  same  is  said  of  the  Malays  and  the  Chinese  by 
Martin,  while  Tommasi-Crudelli  has  noticed  differences  in  the  resisting  power 
of  the  inhabitants  of  certain  localities  in  Italy. 

The  natives  of  the  Philippines,  living  in  the  most  malarial  localities,  enjoy 
an  increased  resistance  to  these  fevers,  a  resistance  which  may  be  broadly 
called  an  acquired  immunity,  for  while  the  plasmodia  are  often  found  in  the 


96 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 


blood,  symptoms  are  absent  or  are  so  slight  as  to  escape  attention.  This 
resistance  to  the  infection  is  very  marked  when  compared  to  the  lack  of 
resistance  shown  by  the  American  troops  stationed  in  the  same  locality.  At 
Camp  Stotsenburg,  out  of  a  brigade  of  American  troops,  over  600  entered  the 
hospital  in  one  month,  suffering  from  initial  attacks  of  malaria;  in  the  native 
population,  which  far  outnumbered  the  troops,  only  a  very  few  cases  of  malaria 
were  observed,  although  the  natives  were  living  under  much  poorer  sanitary 
conditions  and  were  much  more  exposed  to  the  bites  of  mosquitoes.  It  is 
probable,  however,  that  a  very  large  proportion  of  the  natives  would  have  been 
found  infected  had  their  blood  been  examined;  hey  had  simply  acquired,  from 
repeated  attacks,  an  immunity  to  the  malarial  poison  and  therefore  presented 
no  symptoms  of  the  disease. 

The  apparent  immunity  of  native  races  to  malaria  was  unexplained  until 
Koch  made  his  observations  in  Africa  regarding  the  occurrence  of  malaria  in 
native  children.  He  proved  conclusively  that  in  malarial  regions  a  very  large 
proportion  of  infants  and  children  show  the  malarial  plasmodia  in  their  blood, 
even  though  no  symptoms  of  the  disease  be  present,  while,  in  the  majority 
of  instances,  the  blood  of  adults  does  not  show  any  trace  of  malarial  infection. 
From  his  findings  he  concluded  that  the  adult  natives,  in  the  tropics,  are  immune 
to  malaria  because  of  having  suffered  from  repeated  attacks  in  infancy  and 
childhood. 

In  West  Africa  Koch  found  that  100  per  cent,  of  children  under  two  years 
of  age  showed  malarial  plasmodia  in  their  blood  and  that  the  percentage  of 
infections  decreased  with  advancing  age;  thus,  children  from  two  to  five  years  of 
age  showed  48  per  cent,  infected,  and  from  5  to  10  years  23.5  per  cent,  infected, 
while  those  over  ten  years  of  age  were  free  from  infection.  In  Kaiser  Wilhelm's 
Land  (New  Guinea)  his  findings  were  as  follows. 


Place 


Age 


No.  examined       Percentage  infected. 


Bogadjine 

Under  2  years 

10 

8  cases  or  80% 

2  to  5  vears 

12 

5  cases  or  41.6% 

5  to  55  years 

86 

0  cases  or  0% 

Under  2  years 

6 

6  cases  or  100% 

2  to  5  years  

13 

6  cases  or  46.1  % 

5  to  10  years  

17 

4  cases  or  23.5% 

10  to  40  years 

39 

0  cases  or  0% 

In  Java,  according  to  Koch,  of  297  children  examined  under  one  year  of 
age  only  66,  or  22.1  per  cent.,  were  found  infected,  while  of  429  children  over  one 
year  of  age  47,  or  10.9  per  cent.,  were  infected.  It  will  thus  be  seen  that  the 
percentage  of  infections  in  children  varies  in  different  localities,  but  he  claims 
that  the  adult  ratio  is  practically  zero  in  tropical  countries  where  malaria  is 
very  prevalent. 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 


97 


Koch's  results  have  been  confirmed  by  Stephens  and  Christophers  and  by 
James.  Stephens  and  Christophers,  at  Accra,  West  Africa,  found  from  23  to 
90  per  cent,  of  babies  infected;  up  to  eight  years  of  age  20  to  57  per  cent.,  up  to 
12  years  of  age  28  to  30  per  cent.;  and  after  the  twelfth  year  infection  was  found 
to  be  rare.  At  Lagos,  of  children  under  two  years  of  age  50  to  100  per  cent, 
were  infected;  from  two  to  five  years,  40  to  75  per  cent.,  and  from  five  to  ten 
years  25  per  cent. 

James,  in  India,  found  that  the  percentage  of  malarial  infection  among 
native  children  varied  greatly  in  different  localities,  being  zero  in  some  places 
and  as  high  as  86  per  cent,  in  others.  Thus,  at  Mian  Mir,  children  up  to  three 
years  of  age  showed  80  per  cent.,  infected;  up  to  five  years,  66  per  cent  ;  up  to  ten 
years,  50  per  cent.,  while  after  ten  years  none  were  infected.  At  Ennur,  children 
up  to  three  years  of  age  showed  65  per  cent,  infected;  up  to  five  years,  51  per 
cent.;  up  to  ten  years,  46  per  cent.;  and  up  to  fifteen  year',  16  per  cent.  He 
found  no  infection  in  natives  over  fifteen  years  of  age.  He  also  states  that  in  the 
most  malarious  localities  the  immunity  of  the  adult  is  very  apparent,  but  in 
those  localities  in  which  the  malarial  ratio  is  low,  an  immunity  of  the  adult  does 
not  appear  to  be  established. 

The  truth  of  Koch's  assertions  regarding  the  immunity  of  adult  natives  in 
malarial  regions  has  been  seriously  injured  by  the  observations  of  numerous 
investigators,  and  it  may  safely  be  said  that  adult  natives,  in  most  malarial 
regions,  show  plasmodia  in  their  blood  in  a  considerable  percentage  of  those 
examined. 

Hope,  in  Pabna,  found  that  while  922  adult  natives  showed  plasmodia  in 
their  blood,  only  862  children  examined  at  the  same  time  presented  them;  in 
other  words,  that  the  adult  malarial  ratio  was  larger  than  the  malarial  ratio  in 
children. 

Annett,  Dutton,  and  Elliot,  working  in  Nigeria,  obtained  the  results  given 
below: 


Age  of  child 

Per  cent,  infected 

0  to  1  year, 

27-3% 

1  to  2  years, 

63.0% 

2  to  3  years, 

63.0% 

3  to  4  years, 

51-0% 

4  to  5  years, 

48.8% 

5  to  6  years, 

34-8% 

6  to  7  years, 

6.6% 

7  to  8  years, 

27-5% 

8  to  9  years, 

25.0% 

9  to  10  years, 

14-0% 

10  years  and  above, 

10.0% 

98 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 


It  will  be  observed  that  these  investigators  found  10  per  cent,  of  adults 
infected. 

The  following  rules  governing  immunity  in  malarial  regions  may  be  said  to 
be  fairly  well  proven  by  the  observations  of  many  investigators: 

i.  In  severely  infected  regions,  provided  conditions  are  favorable  for  the 
propagation  of  malaria,  a  relative  immunity  is  generally  observed  in  the  adult 
population,  and  is  more  promptly  acquired,  as  more  reinfections  occur  in 
childhood. 

2.  In  slightly  infected  regions  a  relative  immunity  is  not  rapidly  acquired, 
as  fewer  children  are  infected  and  reinfections  are  less  common. 

3.  In  countries  in  which  seasons,  such  as  winter,  occur  which  are  unfavor- 
able to  malaria,  an  acquired  immunity  to  the  disease  is  rarely  observed,  as 
reinfections  are  thus  rendered  less  numerous. 

In  this  connection  the  observations  of  Panse  in  East  Africa  (Tonga)  are  of 
great  interest  as  they  serve  to  show  that  in  some  regions  the  above  rules  do  not 
hold  good.  He  examined  2,227  natives  in  a  highly  malarious  locality  with  the 
following  results: 


Age 

No.  examined 

No.  infected 

Per  cent,  infected 

Under  1  \2  year 

Between  1  /2  and  1  vr 

1  year  of  age    

2  years  of  age     

16 

9 

25 

20 

28 

48 

84 

3i4 

1683 

6 

6 

22 

17 

25 

34 

52 

125 

258 

37-5% 
66.6% 
88.0% 
8^-o% 

3  years  of  age     

89.2% 
70.8% 
61.9% 
39-4% 
15-3% 

Between  4  and  5  yrs 

Between  6  and  7  yrs 

Half-grown  children 

Adults      

Summary:     Of  children  under   1   year  of  age,   48  per  cent,   were  infected. 
Of  children  between  1  and  3  years,  87.6  per  cent,  were  infected. 
Of  children  between  4  and  7  years  of  age,  65.1  per  cent,  were  in- 
fected. 

The  results  given  by  Panse  agree  with  my  own  in  the  examination  of  native 
Filipinos,  and  they  seem  to  me  to  be  more  nearly  correct  than  those  of  Koch,  for 
while  they  undoubtedly  show  a  gradual  diminution  of  the  number  of  cases  of 
infection  with  advancing  age,  they  also  show  that  only  a  certain  proportion  of 
the  adult  population  acquire  an  immunity,  which  I  believe  will  be  found  to  be 
true  of  the  population  of  most  malarial  communities.  It  certainly  is  not  often 
found  to  be  the  case  that  all  the  adults  in  such  a  community  are  immune  to 
malaria,  and,  indeed,  it  is  impossible  to  believe  in  any  such  wide-spread  im- 
munity following  attacks  of  malaria;  yet  Koch  and  others  have  claimed  ab- 
solutely negative  results  in  the  examination  of  the  blood  of  adults  in  malarial 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 


99 


regions.  I  think  it  is  evident  that  such  results  must  be  very  exceptional,  and 
require  the  most  careful  confirmation  before  they  can  be  accepted  as  true  of 
malarial  regions  in  general. 

In  one  of  the  most  malarial  localities  in  the  Philippine  Islands  (Camp 
Stotsenburg)  I  examined  the  blood  of  45  adults  and  180  children,  all  Filipinos, 
and  all  of  whom  at  the  time  of  examination  were  free  from  symptoms  of  malaria. 
I  was  able  to  obtain  the  exact  age  in  but  147  of  the  180  children,  and  only  this 
number  is  included  in  the  table  of  results  which  follows: 


No.  examined 


1  to     5  yrs 

5  to  10  yrs 

10  to  15  yrs, 

Adults 


40 
54 
53 
45 


No.  infected 


3° 
20 

13 
28 


Per  cent,  infected 


72.5% 
3  7  •  o  % 
24-5% 
62.2% 


In  my  examinations  it  will  be  noticed  that  of  the  45  adults  examined,  no  less 
than  62  per  cent,  showed  infection  with  the  malarial  plasmodia,  despite  the  fact 
that  my  examinations  of  the  blood  of  children  demonstrate  that  the  percentage 
of  infections  diminished  with  advancing  age;  this  apparent  contradiction  I  can- 
not explain,  but  it  is  probable  that  a  study  of  the  blood  of  a  larger  number  of 
adults  would  materially  reduce  this  great  percentage  of  infections.  From  the 
results  obtained,  however,  it  is  very  evident  that  the  adult  Filipino  in  this 
locality  has  developed  but  little  immunity  to  the  malarial  fevers,  and  I  think  it 
is  probable  that  these  people  possess  little  or  no  immunity  to  malaria,  although 
in  malarial  localities  such  adults  have  from  childhood  suffered  from  repeated 
attacks  of  the  disease.  I  have  notes  upon  several  native  adults  of  this  region, 
who,  within  two  years,  have  been  admitted  to  the  hospital  from  8  to  16  times 
with  malarial  infection.  This  lack  of  immunity  to  malaria  in  the  native  adults 
of  the  Philippines  appears  to  me  to  be  a  very  significant  and  important  fact 
from  the  standpoint  of  social  economy,  for  it  is  invariably  true  that  a  people 
suffering  from  long-continued  malarial  infection  are  poor  producers,  especially 
along  agricultural  lines,  where  strength  and  endurance  are  demanded.  It  is  a 
fact  that  will  have  to  be  taken  into  account  in  our  endeavors  to  make  this  people 
prosperous,  for  I  am  convinced  that  malarial  infection  is  very  prevalent  among 
them,  often  in  an  insidious  form,  and  that  it  offers  a  serious  barrier  to  effort 
upon  their  part.  The  gratuitous  distribution  of  quinine  to  the  people  of  certain 
districts  of  the  Philippines  would  do  much  toward  increasing  their  capacity  for 
labor. 

From  what  has  been  said  it  is  evident  that  an  acquired  relative  immunity 
against  the  malarial  fevers  is  not  uncommon  under  certain  conditions  and  in 
some  localities,  and  that  it  is  always  due  to  repeated  attacks  of  malarial  infection. 


IOO 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 


The  efforts  that  have  been  made  to  produce  an  artificial  immunity  to  malaria 
will  be  mentioned  in  speaking  of  the  serum  treatment  of  the  disease. 

My  results  concerning  the  proportion  of  infected  adults  in  malarial  regions 
in  the  tropics  have  recently  been  confirmed  by  A.  Plehn,  whose  investigations 
were  conducted  in  Kamerum,  West  Africa.     He  found  as  follows: 


Age 

No.  examined 

No.  infected 

Per  cent,  infected 

Between  2  and  5 

Between  5  and  10 

Adults 

iS 
26 

40 
43 

*7 

24 
34 
26 

94% 
92% 
85% 
60% 

He  concludes  as  the  result  of  his  researches  that  the  adult  West  Coast 
African  negro  is  not  immune  to  malaria,  but  has  established  a  tolerance  to  the 
plasmodia,  as  shown  by  the  fact  that  the  attacks  are  so  mild  as  to  present  no 
characteristic  symptoms.  In  this  way  these  natives  are  relatively  immune  to 
malaria  because  they  have  established  an  immunity  to  the  malarial  toxin  or 
toxins. 

The  Theories  of  Immunity  as  Applied  to  Malaria. — As  is  well  known, 
there  are  two  theories  of  immunity  that  are  supported  by  medical  scientists,  that 
of  Ehrlich  and  that  of  Metchnikoff,  and  each  theory  has  many  able  supporters. 
Both  schools  believe  in  the  various  antibodies,  Metchnikoff  and  his  followers 
believing  that  all  are  produced  by  the  leucocytes,  while  the  school  of  Ehrlich 
does  not  designate  any  specific  body  cell  as  producing  them;  Ehrlich  believes 
that  there  are  many  different  complements,  while  Metchnikoff  believes  that  there 
are  but  two,  microcytase  and  macrocytase,  both  produced  entirely  by  the  phago- 
cytes, and  liberated  by  phagolysis  or  destruction  of  the  phagocytes.  Complement 
has  been  extracted  from  the  leucocytes  by  the  followers  of  both  theories,  so  that 
some  complement,  at  least,  is  produced  by  the  leucocytes.  The  most  enthusiastic 
of  Ehrlich's  followers,  however,  believe  that  complement  only  occurs  in  normal 
blood  serum.  Metchnikoff  also  believes  that  antitoxins  when  introduced  into 
the  body  act  by  stimulation  of  the  phagocytes,  leading  to  increased  absorption 
of  the  toxin  and  consequently  to  its  destruction.  He  is  positive  in  the  belief 
that  immunity  in  every  disease  depends  upon  the  phagocyte. 

The  immunity  in  malaria  must  depend  upon  certain  reactions  between  the 
cells  of  the  tissues  and  the  plasmodia  or  their  toxins;  the  exact  modus  operandi  is 
not  known,  but  may  be  explained  theoretically  by  ether  Metchnikoff's  or 
Ehrlich's  conception  of  the  cause  of  immunity.  The  fact  that  no  malarial  toxin 
has  as  yet  been  discovered  does  not  militate  against  Ehrlich's  theory  as  applied 
to  this  disease,  but  it  is  probable  that  immunity  in  malaria  depends  not  only 
upon  antibodies  evolved  in  the  blood  serum,  but  also  upon  substances  liberated 
during  phagolysis,  and,  to  a  marked  degree,  upon  the  process  of  phagocytosis. 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  IOI 

Whether  the  antibodies  evolved  are  antiplasmodial,  that  is,  capable  of  destroy- 
ing the  plasmodia,  or  antitoxic  in  nature,  or  both,  is  entirely  problematical. 

Causes  of  Natural  Immunity  to  Malaria. — Natural  immunity  to  the 
malarial  fevers  is  comparatively  rare  and  is  individual  in  character.  It 
probably  depends  upon  factors  which  are  operative  in  other  infections,  but  I 
am  inclined  to  believe  that  phagocytosis  is  of  greater  importance  in  malaria  than 
it  is  in  most  other  acute  infections.  The  chief  factors  concerned  in  natural 
immunity  against  the  malarial  fevers  are  probably  the  following: 

i.  Antiplasmodial  and  antitoxic  substances  in  the  blood  serum. 

2.  Antiplasmodial  and  antitoxic  substances  in  the  leucocytes,  which  are 
liberated  by  phagolysis. 

3.  Phagocytosis. 

4.  Absorption  of  toxic  material  by  the  leucocytes. 

5.  Absence  of  specific  cell  receptors. 

6.  Distribution  of  the  cell  receptors  in  non-vital  organs. 

Any  one  or  all  of  these  factors  may  be  concerned  in  natural  immunity  in 
malaria,  and  it  is  not  necessary  to  discuss  here  the  manner  in  which  they  act; 
it  should  be  remembered  that  the  whole  subject  of  the  production  of  immunity 
in  malaria  is  theoretical,  and  we  can  only  reason  from  analogy  with  other 
infectious  diseases. 

Causes  of  Acquired  Immunity  in  Malaria. — As  has  been  shown,  re- 
peated attacks  of  the  malarial  fevers  result  in  an  acquired  relative  immunity  to 
the  disease,  and  this  immunity  may  be  more  or  less  racial  in  character.  This 
condition  may  be  brought  about  by  complex  factors,  the  chief  of  which  are 
probably: 

1.  Production  of  antiplasmodial  and  antitoxic  substances  in  the  blood 
serum. 

2.  Phagolysis  of  leucocytes,  and  consequent  liberation  of  antiplasmodial 
and  antitoxic  substances. 

3.  Overproduction  and  excretion  of  such  substances  by  the  polymorpho- 
nuclear leucocytes. 

4.  Resorption  of  toxin  by  the  leucocytes. 

5.  Phagocytosis. 

The  immunity  observed  in  individuals  after  repeated  attacks  of  malaria  is 
probably  an  acquired  active  antitoxic  immunity,  as  shown  by  the  fact  that  the 
plasmodia  may  be  present  and  undergo  normal  schizogony,  but  no  symptoms  of 
malaria  are  produced.  As  I  have  shown,  this  form  of  immunity  consists  in  a 
relative  tolerance  to  the  presence  of  the  plasmodia  and  their  toxins,  thus  strongly 
indicating  that  such  malarial  toxins  exist  and  that  it  is  possible  for  antitoxic 
substances  to  be  produced  in  the  blood  of  patients  suffering  from  this 
disease. 

The  antiplasmodial  substances  may  consist,  I  believe,  in  both  plasmodi- 
cidal  and  plasmodilytic  agents,  for  it  is  not  uncommon,  during  malarial  attacks, 
to  observe  numerous  extracellular  plasmodia  in  the  blood  serum  undergoing 


102  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

marked  degenerative  changes,  such  as  vacuolation  and  fragmentation.  To 
these  phenomena  the  term  "plasmcdiolysis"  might  well  be  applied. 

While  antiplasmodial  substances  may  be  of  great  importance  in  the 
production  of  immunity  against  malaria,  it  cannot  be  denied  that  phagocytosis 
is  very  common  in  this  disease,  and  undoubtedly  plays  a  very  important  part 
in  the  defense  of  the  organism  against  the  infection. 

The  question  is  often  asked:  Does  one  form  of  malaria  protect  against 
another?  We  have  but  very  little  data  upon  this  point,  although  we  do  know 
that  various  forms  of  the  infection  may  occur  together  or  may  follow  one 
another.  The  question  is  only  of  importance  when  an  immunity  has  become 
established  to  one  form  of  the  disease,  and  regarding  this  we  have  Koch's 
observations  in  the  Bismarck  Archipelago.  Only  one  form  of  malaria,  the 
quartan,  occurs  in  this  Archipelago,  and  many  of  the  natives  have  acquired  an 
immunity  to  this  form.  In  numerous  instances,  however,  Koch  observed  the 
development  of  tertian  and  aestivo-autumnal  malaria  in  these  quartan  immunes 
when  they  visited  places  in  which  these  forms  of  malaria  were  present. 

This  observation  would  appear  to  prove  conclusively  that  immunity  to 
quartan  malaria  does  not  protect  against  either  the  benign  tertian  or  the  aestivo- 
autumnal  fevers.  This  fact  agrees  with  out  conceptions  of  the  specificity 
of  the  various  malarial  plasmodia,  and  would  appear  to  be  a  conclusive  argument 
against  the  unity  of  the  species  which  have  been  described. 


Literature   upon   Methods   of   Transmission   of   Malaria,    Cultivation   of   the 
Plasmodia,  and  upon  Immunity. 

Methods  of  Transmission. 

1877.      Boudin.      Traite  de  geographie  et  de  statisque  medicale,  i,  p.  142,  Par. 

1881.  Tomassi-Crudeli.  Malaria  and  the  Ancient  Drainage  of  the  Roman 
Hill.      The  Practitioner,  xvii,  p.  295. 

1884.  Mariotti  and  Ciarrochi.  Sulla  transmissibilita  dell,  infezione  da  ma- 
laria.     Lo  Sperimentale,  Dec,  s.  iv,  liv,  p.  263. 

1884.      Gerhardt.      Ueber  Intermittens  Impfungen.  Zeitschr.  f.  k.  Med.,  p.  375. 

1887.  Tomassi-Crudeli.  Die  Ursache  der  Malaria.  Deutsch.  med.  Woch., 
Nov.,  No.  46,  p.  992. 

1889.  Antolisei  and  Angelini.  Due  altri  casi  di  febbre  malarica  sperimen- 
tale.     Rif.  Med.,  Sept.  28  and  29,  Nos.  226-227,  pp.  13 52-13 58. 

1889.  Gualdi  and  Antolisei.  Una  quartana  sperimentale.  Rif.  Med., 
Nov.  13,  No.  264,  p.  1580. 

1889.  Gualdi  and  Antolisei.  Inoculazione  della  forme  semilunari.  di 
Laveran.      Rif.  Med.,  Nov.  25,  No.  274,  p.  1639. 

1891.  Di  Mattel  Contributo  alio  studio  dell'  infezione  malarica  sperimentale 
nell'  nomo  e  negli  animali.      Rif.  Med.,  No.  121,  p.  544. 

1 89 1.  Bein.  Aetiologische  und  experimentelle  Beitrage  zur  Malaria.  Charite 
Annalen,  1891,  p.  181. 

1894.  Sacharoff.  Ueber  die  Einfluss  der  Kalte  auf  der  Lebensfahigkeit  der 
Malariaplasmodien.      Cent.  f.  Bakt.,  Feb.  5,  xv,  Nos.  5-6,  p.  158. 

1895.  Baccelli.      Studien  iiber  Malaria.      Berlin. 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  IO3 

1895.      Di    Mattel      Beitrage    zum    Studium  der  experimentellen    malarischen 

Infection  an  Menschen  und  an  Thieren.      Archiv.  f.  Hyg.,  pp-  191-500. 
1900.      Manson.     Patrick.      Experimental     Proof     of     the      Mosquito-Malaria 

Theory.      The  Brit.  Med.  Jour.  Sept.  29,  p.  949. 

(For  literature  concerning  the  transmission  of  malaria  by  the  mosquito 

see  bibliography  given  at  the  end  of  Chapter  III.) 

Literature  upon  Cultivation  of  the  Malarial  Plasmodia. 

1890.  Rosenbach.  Das  Verhalten  der  in  den  Malariaparasiten  enthaltenen 
Kornchen.      Deutsch.  med.  Woch.,  No.  16,  p.  325. 

1890.  Sacharoff.  Ueber  Conservirung  von  Malariaplasmodien  in  lebenden 
Zustande  in  Blutegeln.  Wratsch.,  p.  644. 

1891.  Rosenbach.  Die  Cinsirverung  lebeden  Malariaparasiten.  Berliner 
klin.  Woch.,  Aug.  24,  p.  839. 

1892.  Coronado.  Reproducion  experimental  del  hemotozoaire  de  Laveran. 
Chron.  Medico-Quirurgica  de  la  Habana,  Nov.,  xviii,  No.  22;  Ibid.,  1893, 
xix,  p.  375. 

1897.      Thayer.      Lectures  on  the  Malarial  Fevers,  New  York,  p.  26. 

Literature  upon  Malarial  Immunity. 

1900.      Koch.      Zweiter    Bericht    iiber    die    Thatigkeit    der    Malariaexpedition. 

Deutsch.  med.  Woch.,  No.  5,  p.  88. 
1900.      Stephens  and  Christophers.     Rep.  Malarial.  Com.  Royal  Soc,  Lond., 

1889— 1900.  Series  3,  p.  6. 

1900.  Celli.  Ueber  Immunitat  gegen  Malariainfection.  Cent.  f.  Bakt.,  24, 
No.  3,  p.  107. 

1 90 1.  Idem.  Nochmals  iiber  Immunitat  gegen  Malariainfection.  Cent.  f. 
Bakt.,  25,  p.  300. 

1 90 1.  Annett,  Dutton  and  Elliot.  Report  of  Malaria  Expedition  to  Nigeris. 
Thompson  Yates  Laboratory  Reports,  3,  p.  19. 

1902.  Panse.  Die  Malaria  unter  den  Eingeborenen  in  Tanga.  Archiv.  f. 
Schiffs-  und  Tropenhyg.,  No.  12. 

1903.  Plehn,  A.  Die  acuten  Infectionskrankheiten  bei  den  Negern  der 
aquatorialen  Kiisten  Westafrikas.  Virchow's  Archives,  vol.  clxxiv, 
Supplement.      Ford. 

1905.  Strachan.  Alleged  Negro  Immunity  to  Malaria.  Brit.  Med.  Jour., 
March  18. 

1906.  Plehn,  A.  Ueber  Malaria-Immunitat.  Archiv.  f.  Schiffs- u.  Tropenhyg., 
vol.  x,  No.  2. 

1906.  Craig,  Chas.  F.  Observations  upon  Malaria.  Philippine  Jour,  of 
Science,  vol,  i,  No.  5,  June,  p.  523. 

1907.  Craig,  Chas.  F.  A  Study  of  Latent  and  Recurrent  Malarial  Infection, 
Etc.      Jour,  of  Infectious  Diseases,  vol.  iv,  No.  1,  Jan.,  pp.  108-140. 


CHAPTER  V. 

Predisposing     Causes,    General    and    Local;    Period    of    Incubation    of    the 
Malarial  Fevers;  Congenital  Malaria. 

Predisposing  Causes. — While  the  malarial  plasmodia  are  the  direct 
cause  of  the  malarial  fevers  and  while  the  transmission  of  these  fevers  depends 
entirely,  so  far  as  we  at  present  know,  upon  infected  mosquitoes  belonging  to 
the  Anophellnae,  there  are  certain  factors  which  enter  indirectly  into  the 
etiology  of  malarial  disease,  either  by  favoring  the  development  of  the  plasmodia 
within  man  or  the  mosquito  or  by  favoring  the  development  of  mosquitoes 
capable  of  transmitting  the  disease.  Such  factors  are  known  as  predisposing 
causes  and  may  be  divided  into  general  and  local. 

General  Predisposing  Causes. — General  conditions  predisposing  to  the 
malarial  fevers  are  climate,  locality,  altitude,  time  of  day,  moisture,  character 
of  the  soil,  winds,  rain,  season,  and  atmospheric  conditions. 

Climate. — A  careful  examination  of  the  geographical  distribution  of  the 
malarial  fevers  convinces  us  that  climate  is  of  immense  importance  in  the 
etiology  of  these  fevers.  These  infections  are  most  common  and  pernicious 
in  tropical  regions,  so  that  heat  may  be  considered  as  an  essential  predisposing 
cause  of  the  malarial  fevers.  The  mild  tertian  and  quartan  infections,  while 
common  in  all  malarial  localities,  are  peculiarly  the  fevers  of  the  temperate 
malarial  zones,  while  the  more  severe  and  often  pernicious  aestivo-autumnal 
infections  are  most  common  in  tropical  countries.  Thus  climate  influences 
not  only  the  amount  of  malaria  in  a  locality,  but  also  the  type  of  infection.  In 
temperate  climates  malaria  occurs  only  during  the  warmer  seasons,  while  in 
the  tropics  it  occurs  throughout  the  year,  although  cases  are  more  numerous 
during  certain  periods.  All  climatic  conditions  favoring  the  development  of 
mosquitoes  of  the  genus  Anopheles  act  as  predisposing  causes  of  the  malarial 
fevers,  provided  infected  individuals  are  present,  otherwise  climate  has  no  effect 
whatever  upon  the  prevalence  of  these  fevers,  except  a  local  effect  in  provoking 
an  attack  in  already  infected  individuals. 

Locality. — This  portion  of  our  subject  has  already  been  considered  under 
the  geographical  distribution  of  the  malarial  fevers  and  in  the  chapter  dealing 
with  immunity.  It  has  been  shown  that  the  prevalence  of  malaria  is  greatly 
influenced  by  locality,  and  that  certain  types  of  infection  are  present  most 
frequently  in  certain  limited  regions.  Not  only  are  tertian  and  quartan 
infections  most  common  in  temperate  regions,  but  even  in  such  localities  the 
two  types  vary  in  prevalence,  while  the  prevailing  type  in  most  tropical  regions 

104 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  105 

are  the  aestivo-autumnal  infections.  Climatic  influences  are  not  the  only 
ones  which  operate  in  thus  limiting  the  varieties  of  malarial  infection  in  certain 
localities,  for  it  is  probable  that  the  variety  of  Anopheles  present  is  of  much 
greater  importance  in  regions  in  which  all  the  types  of  malarial  infection  are 
present.  Thus  it  will  be  found,  that  in  regions  in  which  the  benign  tertian 
infections  are  most  prevalent,  especially  if  such  regions  be  situated  in  the 
tropics,  the  prevailing  type  of  Anopheles  present  is  one  that  transmits  Plasmo- 
dium vivax.  As  showing  the  influence  of  locality  upon  the  type  of  malarial 
infection,  the  following  instance  may  be  of  interest: 

At  Camp  Stotsenburg,  Pampanga  Province,  Luzon,  P.  I.,  during  five 
months,  I  observed  386  cases  of  malaria  in  which  the  plasmodia  were  demon- 
strated in  the  blood.  Of  these  cases  98  were  infected  with  the  benign  tertian 
Plasmodium  (Plasmodium  vivax) ;  eight  with  the  quartan  plasmodium  (Plas- 
modium malariae),  and  272  were  infected  with  the  aestivo-autumnal  plasmodia, 
of  which  258  were  infected  with  the  tertian  aestivo-autumnal  plasmodium 
(Plasmodium  falciparum)  and  14  with  the  quotidian  aestivo-autumnal 
plasmodium  (Plasmodium  falciparum  quotidianum) .  There  were  eight  combined 
infections  with  the  benign  tertian  and  tertian  aestivo-autumnal  plasmodia. 

At  Camp  Gregg,  40  miles  distant  from  Stotsenburg,  where  the  climatic 
conditions  were  exactly  similar,  Captain  Chamberlain,  of  the  Army  Medical 
Corps,  during  twelve  months  observed  162  cases  of  malaria  in  which  the  type 
of  plasmodium  was  recognized.  Of  the  162  cases,  83  were  infected  with  the 
benign  tertian  plasmodium,  4  with  the  quartan  plasmodium,  and  75  with  the 
aestivo-autumnal  plasmodia.  At  Camp  Gregg  the  quotidian  aestivo-autumnal 
infections  were  more  prevalent  than  at  Camp  Stotsenburg,  no  less  than  16  of 
the  75  aestivo-autumnal  infections  being  of  this  type. 

From  the  above  it  will  be  seen  that  while  at  Camp  Stotsenburg  the  aestivo- 
autumnal  infections  greatly  outnumbered  other  types,  at  Camp  Gregg  the 
benign  tertian  infections  were  greatest  in  number,  although  climatic  conditions 
were  practically  the  same.  Similar  variations  in  the  type  of  malarial  infection 
have  been  noted  by  numerous  observers  and  can  best  be  explained  by  the 
occurrence  in  such  localities  of  certain  species  of  Anopheles  which  transmit 
only  a  certain  species  of  the  malarial  plasmodium.  Thus  at  Camp  Stotsenburg 
the  mosquitoes  most  prevalent  were  those  that  transmit  the  aestivo-autumnal 
plasmodia,  while  at  Camp  Gregg  the  tertian  transmitting  mosquitoes  were 
most  numerous. 

Altitude. — The  malarial  fevers  occur  especially  in  lowlands  along  the 
coast  and  rivers  of  warm  countries.  This  is  an  etiological  fact  which  has  been 
observed  since  the  very  earliest  study  of  malarial  infections.  Mountainous 
regions  are  generally  free  from  malaria,  although  there  are  many  exceptions 
to  this  rule.  In  the  Philippine  Islands  certain  valleys  are  almost  free  from 
malaria,  while  the  hills  in  the  vicinity  are  notoriously  infected.  In  Italy, 
while  there  are  numerous  examples  of  the  protection  afforded  against  malaria 
by  residence  upon  hills  surrounding  malarious  districts,   Grassi  has  found 


106  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

malaria  present  at  a  height  of  8,400  feet,  while  in  the  Rocky  Mountains  malaria 
has  been  observed  on  the  eastern  slope  at  a  height  of  over  6,000  feet.  It  should 
be  remembered,  however,  that  many  cases  diagnosed  as  malaria  in  the  Rocky 
Mountains,  or  as  mountain  fever,  are  really  cases  of  typhoid  fever. 

In  South  America,  in  the  Andes,  malarial  fevers  have  been  observed  at  an 
elevation  of  10,000  feet.  Elevation  is  a  protection  against  malaria  only  when 
mosquitoes  and  the  conditions  favoring  their  existence  are  absent,  and  where 
these  infections  do  occur  at  high  elevations  it  will  invariably  be  found  that 
the  climatic  and  telluric  conditions  are  favorable  to  the  development  of  these 
insects.  Relapses  of  malarial  infections  acquired  elsewhere  are  common 
in  high  cool  regions  and  this  should  not  be  forgotten,  as  pointed  out  by  Thayer, 
when  malaria  is  reported  in  a  district  supposed  to  be  free  from  the  disease. 
Thayer  has  reported  a  case,  in  which  a  relapse  of  a  benign  tertian  infection 
occurred  while  the  individual  was  traveling  in  a  healthy  portion  of  the  Alps, 
18  months  after  the  last  attack  of  the  fever. 

It  has  been  observed  that  persons  living  in  malarious  localities  and  sleeping 
in  the  lower  stories  of  houses  are  more  apt  to  become  infected  than  those 
sleeping  in  the  upper  stories.  For  a  long  time  this  was  held  to  be  due  to  the 
low-lying,  noxious  "malarial"  vapors  which  penetrated  the  lower  floors 
but  did  not  rise  to  the  upper  stories  of  dwellings.  The  true  explanation  is 
that  mosquitoes  do  not  fly,  as  a  rule,  to  any  great  height,  and  thus  those  persons 
sleeping  in  the  lower  stories  of  dwellings  are  more  frequently  bitten. 

Time  of  Day. — It  has  always  been  observed  that  there  is  much  more 
danger  of  contracting  malaria  at  night  than  during  the  day,  a  fact  formerly 
attributed  to  the  malarial  gases  and  vapors  which  arise  over  damp  ground 
during  the  hours  of  night.  In  the  light  of  our  present  knowledge  of  the  method 
of  transmission  of  these  fevers  the  fact  is  easily  explained,  for  the  mosquitoes 
that  transmit  the  disease  are  nearly  all  night  feeders,  and  do  not  bite,  as  a  rule, 
until  after  dark  or  during  twilight. 

Moisture. — Moisture  is  absolutely  essential  for  the  propagation  of 
malaria,  as  water  is  necessary  for  the  development  of  the  ova  of  mosquitoes. 
Marshes  and  low-lying  damp  regions  are  usually  conducive  to  malaria,  and 
where  malaria  is  most  prevalent  there  moisture  is  found  in  abundance.  Even 
in  the  most  malarial  of  tropical  regions  a  short  wet  season  is  followed  by  a 
great  decline  in  malarial  infection  and  a  total  disappearance  of  the  disease 
when  there  is  a  prolonged  draught.  The  influence  of  moisture  is  explained  by 
the  fact  that  mosquitoes  are  most  numerous  and  breed  most  abundantly  in 
moist  regions. 

Character  of  the  Soil. — The  geological  formation  of  the  soil  is  of  very 
great  importance  in  the  prevalence  of  malaria.  An  impervious  subsoil  is  a 
predisposing  cause  of  malaria  in  that  it  favors  the  production  of  stagnant  pools 
and  collections  of  water  in  which  mosquitoes  may  breed.  Tropical  jungles,  low 
marshy  lands,  or  lands  covered  with  stagnant  pools  of  water  are  most  apt  to 
be  malarious  not  because  of  the  character  of  the  soil,  but  because,  as  Mar- 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  107 

chiafava  well  says,  "beneath  a  more  or  less  thick  stratum  of  humus  there  is  an 
impervious  layer"  which  gives  rise  to  pools  of  water  and  general  moisture  of  the 
soil.  From  the  days  of  the  earliest  Romans,  who  constructed  extensive  drainage 
canals,  up  to  the  present  time,  it  has  been  recognized  that  thorough  drainage  of 
a  malarial  region  resulted  in  the  disappearance  of  the  disease,  but  it  was  not 
until  the  discovery  of  the  relation  of  the  mosquito  to  malarial  transmission  was 
announced  that  we  had  any  adequate  explanation  of  this  fact. 

While  the  porosity  of  the  soil  is  obviously  of  great  importance,  the  con- 
formation of  the  soil  is  of  still  greater,  as  this  determines  the  regulation  of  the 
moisture.  Even  though  pools  be  formed,  if  the  conformation  is  such  that  they 
can  be  quickly  drained,  malaria  may  not  be  prevalent,  as  the  ova  of  the  mos- 
quitoes do  not  have  time  to  develop;  on  the  other  hand,  if  the  conformation  be 
such  that  water  collects  in  pools  and  hollows  which  cannot  be  drained,  then 
malaria  may  become  prevalent. 

While  moisture  and  the  collection  of  water  in  pools  sufficiently  large  to 
enable  the  larvae  of  mosquitoes  to  breed  is  essential  to  the  prevalence  of-  malaria, 
these  fevers  may  occur  in  regions  in  which,  at  first  glance,  the  character  of  the 
soil  would  indicate  that  such  an  occurrence  would  be  impossible.  Lutz  has 
proven  that  certain  species  of  Anophelinae  may  develop  in  collections  of  water 
formed  between  the  leaves  of  trees  or  plants  in  tropical  and  subtropical  regions, 
and  that  extensive  malarial  infection  may  exist  where  the  common  breeding- 
places  of  these  mosquitoes  are  absent.  In  many  localities  noted  for  the  preva- 
lence of  malaria  the  soil  may  be  dry  and  no  breeding  places  of  mosquitoes  be 
apparent,  but  close  inspection  will  reveal  the  fact  that  Anopheles  are  present, 
breeding  probably  at  some  distance  from  the  infected  locality,  in  small  jungle 
pools  or  in  artificial  collections  of  water  about  the  quarters  of  the  natives  living 
in  the  vicinity.  This  is  the  case  at  Camp  Stotsenburg,  in  the  Philippine  Islands, 
where  malaria  was  so  prevalent  that  it  had  to  be  abandoned  as  a  brigade  post. 
The  soil  is  volcanic  in  nature,  and  even  after  the  heaviest  rains,  becomes  per- 
fectly dry  in  a  few  hours.  There  is  no  stagnant  water  within  one  mile  of  the 
post,  and  no  breeding-places  of  Anopheles.  Still  these  insects  are  numerous  at 
times  and  as  they  must  fly  at  least  a  mile  before  reaching  the  post,  it  will  be  seen 
that  in  this  instance  the  prevalent  idea  that  they  fly  but  a  short  distance  is 
disproved.  It  was  invariably  found  that  when  the  grass  about  Camp  Stotsen- 
burg was  allowed  to  grow  to  any  length  the  number  of  mosquitoes  increased, 
with  a  coincident  rise  in  a  number  of  cases  of  malarial  infection;  on  the  other 
hand,  when  it  was  cut,  both  mosquitoes  and  malaria  diminished  very 
appreciably. 

In  this  instance,  while  the  soil  of  the  infected  region  could  not  be  considered 
as  a  predisposing  factor  in  the  prevalence  of  malaria,  the  soil  of  the  region  sur- 
rounding the  Camp  and  the  carelessness  of  the  natives  regarding  the  artificial 
collections  of  water  about  their  houses  resulted  in  severe  infection  of  an  area  in 
which  mosquitoes  could  not  breed  but  which  they  could  reach  by  flying. 

The  building  of  canals,  railways,  harbors,  and  extensive  military  works; 


108  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

plowing  and  ditching;  the  clearing  of  land  and  the  construction  of  highways, 
have  often  been  followed  by  outbreaks  of  malaria  among  the  workmen  and  the 
inhabitants  of  the  surrounding  country.  This  was  formerly  attributed  to  the 
turning  up  of  the  soil  and  the  consequent  liberation  of  "malarial"  gases,  but  we 
know  now  that  such  operations  favor  malaria  only  inasmuch  as  suitable  breed- 
ing-places for  mosquitoes  are  formed,  water  collecting  in  the  holes  and  hollows 
inevitably  produced  during  extensive  work  involving  the  digging  up  of  the  soil. 
In  regions  where  neither  the  suitable  mosquito  or  infected  individuals  are 
present,  such  operations  are  never  followed  by  the  appearance  of  the 
disease. 

The  character  of  the  soil  is  of  little  importance  so  long  as  breeding-places 
for  mosquitoes  are  not  present,  the  question  of  soil  in  relation  to  malaria 
depending  entirely  upon  the  relation  which  it  bears  to  the  propagation  of  the 
malarial  mosquitoes. 

Winds. — Some  authorities  have  considered  that  the  malarial  fevers  may 
be  transmitted  by  the  winds,  Scheube  stating  that  "when  they  blow  over 
marshes  or  other  sources  of  malaria  they  may  carry  the  disease  to  fever-free 
spots.  I  believe  that  such  an  occurrence  is  so  rare  as  to  be  of  no  practical  im- 
portance, as  it  is  obvious  that  winds  can  only  transmit  malaria  by  blowing 
infected  mosquitoes  to  uninfected  localities,  and  it  is  a  well-known  fact  that  these 
insects  hide  in  the  grass  and  beneath  foliage  when  winds  are  blowing.  A  few 
instances  are  recorded  where  winds  appear  to  have  transmitted  malaria  by 
transmitting  infected  mosquitoes.  Thus  Brunnhoff  mentions  an  epidemic  of 
malaria  upon  a  German  ship  lying  two  miles  away  from  a  malarial  coast, 
although  none  of  the  crew  had  visited  the  shore.  Such  an  epidemic  can  only  be 
explained  by  supposing  that  infected  mosquitoes  reached  the  vessels,  pre- 
sumably by  action  of  the  wind,  as  two  miles  is  a  much  longer  distance  than  these 
insects  usually  fly. 

If  is  probable,  however,  that  winds  exercise  a  considerable  protective  in- 
fluence against  malaria,  as  mosquitoes  do  not  fly  about  when  the  wind  is  blow- 
ing. It  is  a  common  observation  in  the  tropics  that  on  windy  days  mosquitoes 
are  seldom  troublesome,  whereas  in  the  same  locality,  upon  still  days,  these  in- 
sects may  be  so  numerous  as  to  render  life  a  burden. 

Rain. — Rain  favors  the  production  of  malaria  because  it  favors  the  breed- 
ing of  mosquitoes.  Added  to  this,  rainy  weather,  by  diminishing  the  resisting 
powers  of  the  individual,  favors  the  development  of  the  disease  in  that  individual 
after  he  has  become  infected  by  the  mosquito.  In  the  tropics  the  malarial 
fevers  are  especially  prevalent  during  and  immediately  after  the  rainy  season, 
and  in  the  temperate  zones  a  dry  spring  is  followed  by  a  decrease  in  the  number 
of  cases  of  malaria  in  an  infected  locality.  In  many  regions,  however,  where 
abundant  rains  occur,  malaria  is  rare,  even  though  the  Anophelinae  are  present. 
This  is  explained  by  the  fact  that  in  such  regions  the  rains  are  so  heavy  and  con- 
tinued that  the  breeding  places  of  mosquitoes  are  washed  out  and  the  ova  and 
larvae  do  not  have  a  chance  to  develop,  or  that  no  infected  individuals  are 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 


I09 


resident  in  the  locality.  In  the  former  instance  an  unusually  heavy  rainfall  may 
act  as  a  protection  against  malaria. 

Season. — Malaria  may  justly  be  considered  as  a  seasonal  disease.  This  is 
so  because  the  insects  transmitting  these  fevers  require  a  certain  amount  of 
heat  and  moisture  in  order  to  develop,  and  these  conditions  are  fulfilled  only 
during  certain  seasons  of  the  year.  Added  to  this  we  know  that  the  malarial 
plasmodia  will  undergo  development  only  in  the  stomachs  of  mosquitoes  living 
under  proper  conditions  as  regards  temperature,  it  having  been  proved  by 
Jancso  that  the  oocysts  develop  best  at  a  temperature  of  between  200  and  300  C, 
while  if  the  temperature  be  lower  than  160  C.  the  organisms  perish. 

In  temperate  regions  initial  attacks  of  the  malarial  fevers  occur  only  during 
the  warm  months,  while  in  the  tropics  these  fevers  occur  throughout  the  year, 
although  even  in  such  regions  a  marked  seasonal  variation  is  observed.  Not 
only  does  the  season  of  the  year  profoundly  influence  the  number  of  cases  of 
malaria  observed  in  a  given  locality,  but  it  also  influences  the  type  of  infection 
present  at  various  times.  In  temperate  regions  the  benign  tertian  fever  occurs 
in  the  spring  and  early  summer  months  almost  alone,  the  quartan  and  aestivo- 
autumnal  fevers  beginning  to  appear  in  July  and  August,  and  being  most 
numerous  during  September  and  October,  at  which  time  the  benign  tertian 
fever  cases  have  diminished  in  number.  In  the  tropics  this  difference  in  type 
as  related  to  season  is  not  so  marked,  although  the  aestivo-autumnal  types  are 
more  common  in  the  late  summer  and  autumn  months  than  at  other  seasons. 
In  both  temperate  and  tropical  regions  cases  of  malaria  are  observed  throughout 
the  year,  but  the  cases  occurring  in  the  early  spring  are  almost  without  excep- 
tion instances  of  relapse,  and  most  of  those  occurring  in  the  tropics  during  the 
latter  portion  of  the  dry  season  are  of  the  same  character. 

The  seasonal  variation  in  malaria  observed  in  different  countries  is  re- 
markable and  at  first  sight  difficult  of  explanation  until  we  remember  the 
method  of  transmission  of  these  fevers,  which  in  each  locality  depends  entirely 
upon  local  conditions  as  regards  climate  and  other  factors  influencing  the 
propagation  of  malarial  mosquitoes. 

As  illustrating  the  influence  of  season  upon  the  prevalence  of  these  fevers  in 
different  localities  the  following  tables  are  given:  In  Baltimore  this  subject  has 
been  thoroughly  studied  by  Thayer  and  the  following  table  given  by  him 
illustrates  the  effect  of  season  upon  the  total  number  of  cases  of  malaria  occurring 
in  that  city,  and  also  the  variation  in  the  type  of  malarial  infection. 


Type 

Jan. 

Feb. 

Mar. 

Apr. 

May 

June 

July 

Aug. 

Sept. 

Oct. 

Nov. 

Dec. 

12 
3 
5 
0 

12 

1 
1 
1 

28 
0 
2 

1 

Si 

1 
S 
0 

76 
0 
2 
0 

68 
0 
3 

1 

131 

3 

37 

3 

161 

0 
99 

3 

153 

2 
191 

4 

168 

1 

203 

11 

54 
4 

63 
6 

17 
2 

22 
2 

Quartan 

Total 

20 

IS 

31 

57 

78 

72 

174 

263 

3SO 

383 

127 

43 

no 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 


From  the  table  it  will  be  seen  that  the  malarial  season  is  at  its  height  in 
Baltimore  during  the  months  of  August,  September,  and  October,  the  great 
increase  in  the  number  of  cases  at  this  time  being  due  to  the  aestivo-autumnal 
fevers.  It  will  also  be  noted  that  the  benign  tertian  type  occurred  during  the 
spring  and  early  summer  months. 

The  following  table  given  by  Celli  includes  93,000  cases  of  malaria  ob- 
served in  hospitals  in  Rome  and  well  illustrates  the  seasonal  variation  of  these 
fevers  in  Italy.  As  in  Baltimore,  the  greatest  number  of  cases  was  observed 
during  the  months  of  August,  September,  and  October,  but  a  marked  decrease 
occurred  during  the  months  of  June,  which  is  not  true  of  the  fevers  of  Baltimore. 
Celli  concludes,  and  I  think  rightly,  that  most  of  the  fevers  occurring  up  to 
June  are  relapses,  with  the  exception  of  the  benign  tertian  cases,  and  concludes 
"the  true  malarial  season  is  in  the  second  half  of  the  year;  its  duration  varies 
in  different  years;  relapses  occur  during  the  whole  of  the  first  six  months  of  the 
following  year,  gradually  declining  from  January  to  June." 


Months 


Years 


1864  1865  1873  1874  1877  1878  1892  1893  1894  1895  1896  1897  1 


Total 


January . . 
February . 
March. .  .  . 

April 

May 

June 

July 

August . .  . 
September 
October .  . 
November 
December 

Total 


284 

195 

228 

198 

189 

170 

168 

151 

112 

114 

83 

88 

439 

340 

1492 

57° 

1056 

476 

775 

437 

431 

475 

271 

205 

853 

681 

711 1 

653 

669 

409 

1135 

2824 

2185 

1761 
1280 

777 


595 

528! 

747 

675 

584 

331 

865 

2647 

2019 

173  2 

1186 


661 

543 

502 

576 

5°4 

375 

1858   398 

2373  1604 

1995  1896 

1460  1495 

795  1245 

695'  ii93 


638 
519 
544 
564 
480 
339 


240 

189 

249 

236 

314 

129 

177 

125 

163 

175 

243 

94 

231 

119 

125 

Ib5 

2  44 

98 

223 

148 

157 

180 

235 

115 

244 

JI9 

159 

IOS 

229 

120 

205 

119 

138 

150 

155 

88 

608 

553 

813 

582 

5°2 

320 

694 

741 

761 

1298 

1181 

939 

410 

586 

984 

1357 

684 

505 

500 

911 

855 

1191 

532 

403 

404 

831 

678 

898 

361 

215 

311 

427 

427 

767 

252 

137 

4423 

5043 

6046 

6947 

4690 

2634 

90 

58 

61 

76 
76 

73 
43i 
905 
799 
703 
732 
386 


4673 

3732 

3906 

3921 

3575 

2553 

8844 

17678 

15203 

J27S5 

9531 

6621 


In  tropical  regions  the  seasonal  variation  of  malaria  is  as  marked,  as  re- 
gards the  number  of  cases,  as  in  temperate  regions,  but  not  as  regards  the  type 
of  malaria,  the  aestivo-autumnal  fevers  being  predominant  in  most  localities 
throughout  the  year.  The  seasonal  variation  in  the  tropics  depends  upon  the 
character  of  the  wet  and  dry  seasons  and  varies  considerably  in  different  locali- 
ties, and  in  different  years.  The  following  table  illustrates  the  seasonal  varia- 
tion in  malaria  at  Camp  Stotsenburg,  Island  of  Luzon,  Philippine  Islands, 
while  the  two  tables  following  show  the  variation  at  Camp  Gregg,  forty  miles 
from  Stotsenburg. 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 


Ill 


Table  showing  seasonal  variation  in  cases  of  malaria  at  Camp  Stotsenburg, 
Luzon,  P.  I. 


Year 

Month 

Number  of  Cases 

i9°4 

August     

September      .  .  . 

24 

57 
24 

58 

75 

76 
27 
20 
10 
14 
17 
1 1 
29 
31 
43 
54 

October    

November 

December     

January    

February 

March 

April 

May    

June    

July    

August      

September      .  .  . 

October    

November 

December     

Total     

386 

Tables  showing  the  seasonal  variation  in  malaria  at  Camp  Gregg,  Luzon, 
P.  I.  Compiled  by  Major  Chamberlain,  U.  S.  Army. 


TABLE  A 

TABLE 

B. 

Year 

Month 

No.  of  Cases                    Year 

Month 

No.  of  Cases 

i9°4 

January 

2                           1903 .... 

January 

27 

February 

4 

February 

21 

March  .  . 

6 

March  .  . 

8 

April  .  .  . 

6 

April  .  .  . 

12 

May    .  .  . 

1 

May    .  .  . 

9 

June    .  .  . 

2 

June    .  .  . 

11 

July    ... 

6 

July    ... 

.|           16 

August 

20 

August 

13 

Septembe 

r.           23 

Septembe 

r.           14 

October 

33 

October 

8 

Novembei 

r.           41 

Novembei 

3 

December 

18 

December 

6 

112  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

In  considering  the  table  of  malarial  infections  at  Camp  Stotsenburg,  it 
will  be  observed  that  while  the  malarial  fevers  are  present  throughout  the  year, 
they  begin  to  increase  in  September,  that  the  greatest  number  of  cases  occur 
during  the  months  of  November,  December,  and  January,  and  that  a  marked 
decrease  commences  in  Februrary  and  March.  The  increase  commences 
toward  the  latter  portion  of  the  rainy  season  in  this  part  of  the  Philippines,  and 
the  greater  number  of  cases  occur  just  following  this  season,  and  at  this  time 
mosquitoes  are  most  numerous.  At  Camp  Gregg  the  malarial  season  differs 
from  that  at  Camp  Stotsenburg,  as  shown  by  Tables  A  and  B,  and  this  difference 
must  be  due  to  local  conditions,  as  the  seasons  are  the  same  in  both  places. 
It  will  thus  be  seen  that  we  should  be  conservative  in  drawing  conclusions 
regarding  the  seasonal  occurrence  of  malaria  in  different  regions  based  upon 
the  occurrence  of  malaria  in  any  particular  region,  as  these  fevers  are  local 
diseases  and  what  is  true  regarding  their  occurrence  in  one  locality  may  be 
very  erroneous  in  another. 

However,  I  believe,  from  observations  made  both  in  this  country  and  in 
the  tropics,  that  the  aestivo-autumnal  infections  are  most  numerous  in  the 
late  summer  and  autumn  months,  and  that  even  in  the  tropics  these  fevers 
observe  a  seasonal  variation  almost  as  marked  as  in  temperate  regions.  While 
in  the  tropics  of  the  aestivo-autumnal  types  occur  throughout  the  year,  it 
has  been  my  exeprience  that,  at  least  in  Cuba  and  the  Philippine  Islands,  these 
fevers  begin  to  increase  in  number  during  August,  and  reach  their  maximum 
during  December  and  January,  most  of  the  cases  observed  during  the  early 
spring  and  summer  being  relapses  rather  than  initial  infections. 

Atmospheric  Conditions. — Certain  atmospheric  conditions  act  as  pre- 
disposing causes  of  malaria  in  so  far  as  they  encourage  the  propagation  of 
mosquitoes  or  deplete  the  health  of  infected  individuals.  In  considering  the 
relation  of  climate,  season,  winds,  and  rains  to  malaria,  some  of  the  more 
important  of  these  conditions  have  been  mentioned,  but  certain  of  them  deserve 
a  more  extended  notice. 

As  mentioned,  temperature  exercises  a  marked  influence  upon  the  preva- 
lence of  malaria,  these  fevers  being  most  abundant  during  the  warm  months 
of  the  year.  While  this  is  so,  the  correlation  between  malaria  and  temperature 
is  a  complex  problem  and  there  are  exceptions  to  the  general  rule  that  are 
difficult  of  explanation.  Celli  calls  attention  to  the  fact  that  in  the  province 
of  Rome  during  1879  malaria  was  more  prevalent  than  for  eight  years,  but  the 
mean  temperature  was  the  lowest  of  these  years;  the  rainfall  in  the  months  of 
March,  April,  and  May  was  the  highest  of  these  years,  and  it  is  probable  that 
mosquitoes  were  more  numerous.  Many  apparent  contradictions  to  the 
influence  of  temperature  are  explained  by  the  habits  of  the  various  species  of 
malaria  transmitting  mosquitoes  and  by  certain  local  conditions  affecting  their 
development. 

Atmospheric  depressions,  by  producing  moisture  of  the  ground, 
are  of  importance  in   the   etiology  of  the   malarial  fevers,  for,  as  has  been 


THE    ETIOLOGY    OF    THE    MALARIAL   FEVERS.  113 

mentioned,  these  fevers  are  most  common  where  the  soil  is  moist,  thus  affording 
opportunities  for  the  breeding  of  the  malarial  mosquitoes.  It  should  be  remem- 
bered, however,  that  no  condition  of  the  atmosphere  per  se  is  capable  of  produc- 
ing malarial  infection,  but  that  the  atmosphere  is  of  importance  only  as  a 
predisposing  factor  in  the  presence  of  infection  or  as  it  favors  the  propagation 
of  the  insects  transmitting  the  disease. 

Local  Predisposing  Causes  of  the  Malarial  Fevers. — Among  local 
conditions  which  may  act  as  predisposing  causes  of  the  malarial  fevers  may 
be  mentioned  the  following: 

1.  Race. — The  occurrence  of  these  fevers  in  regard  to  different  races  has 
been  discussed  in  the  chapter  dealing  with  immunity,  and  there  it  has  been 
shown  that  the  relative  immunity  enjoyed  by  certain  dark-skinned  races  in 
malarial  localities  is  the  result  of  repeated  infections  during  childhood  and 
early  adult  life.  That  people  inhabiting  malarial  regions  are  less  susceptible 
to  infection  than  new-comers  is  a  fact  that  cannot  be  disputed,  but  the 
examination  of  the  blood  of  such  persons  will  often  result  in  the  demonstration 
of  the  plasmodia,  although  no  symptoms  of  infection  are  present.  In  this  case 
there  is  no  immunity  to  the  plasmodia,  but  rather  to  the  effects  of  the  parasites. 
Thayer  and  Hewetson  have  shown  in  the  United  States  that  the  negro  is 
relatively  less  liable  to  malaria  than  the  whites,  the  relative  susceptibility 
of  the  negro  being  nearly  two-thirds  less.  According  to  Hirsch,  the  Caucasian 
race  is  more  susceptible  to  malaria  than  any  other,  and  it  is  undoubtedly  true 
that  the  white  man  recently  arrived  in  malarial  regions  of  the  tropics  develops 
the  disease  promptly  while  the  dark-skinned  races  escape  for  long  periods  of 
time.  It  is  probable  that  the  thicker  skin  of  the  negro  and  of  the  Malay, 
as  well  as  the  use  of  grease  or  oil,  together  with  the  natural  odor  of  the  skin, 
may  be  of  importance  in  protecting  these  races  from  the  bites  of  mosquitoes. 

Those  individuals  residing  in  a  malarial  locality  present  the  more  chronic 
forms  of  infection,  while  new  arrivals  present  the  acute  and  severe  types. 
Scheube  claims  that  in  Europeans  the  quotidian  or  remittent  types  of  malaria 
are  most  common,  while  the  natives,  or  less  predisposed  races,  show  the 
benign  tertian  and  quartan  forms  of  fever.  This  has  not  been  my  experience 
in  Cuba  or  in  the  Philippines,  for  I  have  observed  aestivo-autumnal  infections 
as  frequently  in  the  natives  as  in  Americans,  and  the  tertian  and  quartan 
fevers  more  frequently  in  newly  arrived  American  soldiers. 

2.  Sex. — When  equally  exposed  both  sexes  present  the  same  ratio  of 
infection,  but,  as  a  matter  of  fact,  malaria  is  more  common  in  men  than  in 
women,  as  the  latter  are  not  as  often  exposed  to  the  bite  of  the  mosquito.  In 
those  countries  in  which  the  women  work  in  the  fields  and  are  exposed  during 
the  late  afternoon  and  the  night  to  the  bites  of  these  insects,  malaria  is  as  common 
in  the  women  as  in  the  men,  while  in  the  case  of  babies  and  young  children  there 
is  no  appreciable  difference  as  regards  sex.  Parturition  has  been  regarded  by 
some  as  a  predisposing  cause  of  malaria,  but  the  evidence  is  not  satisfactory, 
although  I  have  observed  cases  in  which  the  strain  of  this  period  has  made 


114  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

manifest  an  already  existing  infection.  In  malarial  regions  the  appearance  of 
fever  after  childbirth  should  always  lead  to  the  examination  of  the  blood, 
and  not  infrequently  it  will  be  found  that  the  symptoms  are  due  to  malaria. 
Pregnancy  exercises  no  protective  influence  against  malaria  and  a  severe 
attack  of  any  of  the  malarial  fevers  in  the  later  months  of  pregnancy  may  be 
followed  by  miscarriage. 

While  under  similar  conditions  sex  has  no  influence  as  regards  malarial 
infection,  it  is  of  some  importance  in  the  prognosis  of  these  fevers.  It  has 
been  my  experience,  as  well  as  that  of  Davidson,  that  in  native  races  more 
fatal  cases  of  malaria  are  observed  among  women  than  among  men,  and  among 
female  children  than  among  male  children.  In  the  Philippine  Islands  I 
observed  that  almost  all  of  the  children  dying  from  malarial  infections  were 
females  and  that  male  children  presented  less  marked  symptoms  than  female. 

3.  Age. — Children  are  more  susceptible  to  infection  than  adults,  and 
the  younger  the  child  the  more  susceptible  it  is.  This  has  been  well  proven 
by  the  observations  of  Koch,  Stephens  and  Christophers,  Annett,  Dutton,  and 
Elliott,  and  others,  in  their  studies  of  malarial  infection  among  the  natives 
of  various  regions.  My  own  observations  in  the  Philippines  also  show  that 
young  children  are  more  susceptible  than  older  ones,  but  that  in  this  instance 
the  adults  suffer  from  malaria  as  much,  or  even  more,  than  do  the  children. 
Old  age  is  protective  in  malarial  localities  because  of  the  development  of  a 
relative  immunity  due  to  repeated  attacks  in  childhood  and  early  adult  life. 

4.  Occupation. — The  occupation  of  man  becomes  a  predisposing  factor  in 
the  production  of  these  fevers  in  proportion  to  the  chances  that  occupation  gives 
him  of  infection  by  the  mosquito.  Laborers  working  at  ditching,  railway 
building,  and  other  occupations  which  necessitate  exposure  to  the  night  air  and, 
therefore,  to  mosquitoes,  are  especially  liable  to  contract  these  fevers.  An 
instance  of  this  was  the  terrific  mortality  from  aestivo-autumnal  malaria  during 
the  French  work  upon  the  Panama  Canal. 

5.  Social  and  Hygienic  Conditions. — The  poor  are  the  greatest  sufferers 
from  malaria  because  they  are  not  as  well  nourished  and  are  not,  as  a  rule, 
protected  from  the  bites  of  mosquitoes.  This  is  well  illustrated  in  tropical 
countries  where  the  native  suffers  greatly  from  malaria  in  the  same  locality  in 
which  the  well-to-do  white  escapes  by  reason  of  better  hygienic  conditions  and 
measures  taken  to  prevent  mosquito  bites.  Celli  has  studied  this  phase  of  the 
subject  very  thoroughly  in  Italy  and  has  shown  that  the  social  condition  of  the 
Italian  peasant  is  indirectly  responsible  for  the  ravages  of  malaria  in  that 
country.  Because  of  improper  food,  miserable  housing,  insufficient  and  bad 
clothing,  and  excessive  work,  the  unfortunate  peasant  of  Italy  falls  an  easy 
victim  to  malaria,  and  what  is  true  in  that  country  is  equally  true  of  every 
region  where  these  fevers  are  prevalent  and  poverty  exists. 

Bad  sanitary  conditions  predispose  to  malaria  by  depleting  the  health  and 
encouraging  the  propagation  of  the  mosquito  which  acts  as  the  agent  of  trans- 
mission.    A  careful  police  of  private  grounds  in  malarial  regions  should  be 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  115 

insisted  upon,  and  particular  attention  should  be  paid  to  the  character  of  habita- 
tions and  the  food  supply  of  the  people.  Malaria  is  purely  an  economic 
question,  and  can  be  controlled  by  any  community  willing  to  spend  the  time 
and  mnoey  necessary  for  the  accomplishment  of  this  end. 

6.  Other  Conditions  Influencing  Infection. — There  are  numerous 
other  factors  that  contribute  to  the  production  of  malarial  fevers,  among  which 
may  be  mentioned  previous  ill  health  and  all  those  conditions  which  lower  the 
individual's  resisting  powers,  such  as  exposure  to  heat,  cold,  and  excessive 
moisture;  dissipation,  overeating,  overwork,  either  mental  or  physical;  loss  of 
sleep,  severe  operations,  and  in  short,  anything  which  interferes  with  the  normal 
physiological  processes.  There  can  be  no  doubt  that  an  infection  with  a  small 
number  of  malarial  plasmodia  is  overcome  in  a  great  many  instances  by  the 
healthy  individual,  but  should  the  normal  resisting  powers  be  lowered  such  an 
infection  would  result  in  the  symptoms  of  the  disease. 

The  Occurrence  of  Malaria  in  Uninhabited  Regions. — Certain  instances 
are  of  record  in  which  .malaria  has  been  reported  as  prevalent  in  regions  unin- 
habited by  man.  Such  regions  have  been  reported  in  Africa  and  India,  and  a 
number  of  theories  have  been  evolved  in  order  to  account  for  the  malaria  of 
these  regions.  The  discovery  by  Dionisi  of  a  plasmodium  in  the  blood  of  bats 
very  closely  resembling  human  plasmodia,  and  by  Koch  of  a  plasmodium  in 
monkeys  almost  identical  morphologically  with  the  benign  tertian  plasmodium 
of  man,  has  led  some  observers  to  consider  that  the  human  plasmodia  are 
capable  of  existence  in  certain  other  animals,  and  that  man  is  infected  by 
mosquitoes  who  have  acquired  their  infection  from  these  animals.  Manson 
suggests  the  possibility  that  the  malarial  plasmodia  may  pass  from  mosquito 
to  mosquito  through  the  infection  of  the  mosquito  egg  by  the  sporozoites,  and 
that  the  cycle  thus  established  may  continue  indefinitely,  thus  accounting  for  the 
development  of  malaria  in  regions  uninhabited  by  man. 

While  it  is  perhaps  too  early  to  be  dogmatic  upon  this  subject,  I  believe  the 
concensus  of  opinion  is  that  malaria  can  only  be  transmitted  to  man  by  the 
bite  of  an  infected  mosquito  that  has  derived  its  infection  from  man,  and  that 
the  occurrence  of  malaria  in  regions  in  which  infected  man  is  absent  is  not 
proven,  and  so  far  as  our  present  knowledge  goes  would  appear  to  be  impossible. 

The  Incubation  Period  of  the  Malarial  Fevers. — We  possess  but  little 
definite  knowledge  of  the  incubation  period  of  the  malarial  fevers  when  natur- 
ally acquired,  but  it  is  safe  to  say  that  it  must  vary  very  greatly  in  individual 
cases.  We  know  from  experience  that  the  plasmodia  may  be  demonstrated  in 
the  peripheral  blood  for  days,  and  even  weeks,  before  the  development  of 
symptoms  of  the  disease,  and  that  such  instances  of  latency  are  not  uncommon. 
We  do  possess,  however,  a  considerable  mass  of  data  regarding  the  incubation 
period  of  these  fevers  after  the  direct  inoculation  of  infected  blood,  and  after 
experimental  infection  by  the  bites  of  mosquitoes. 

The  Incubation  Period  after  the  Direct  Inoculation  of  Infected 
Blood. — In  a  previous  chapter  I  have  shown  that  the  malarial  fevers  are  in- 


n6 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 


oculable  from  man  to  man  by  the  injection  of  blood  from  an  infected  individual 
into  a  healthy  one.  The  period  of  incubation  of  the  various  types  of  malaria 
following  this  procedure  is  given  in  the  table  that  follows,  together  with  the 
name  of  the  observer  and  the  species  of  plasmodium  inoculated. 


Period  of 

Observe: 

Species  Inoculated 

Incubation 

Type  of  Fever 

Antolisei  and 

Ange- 

lini. 

Tertian. 

ii  days. 

Tertian. 

Antolisei  and 

Ange- 

lini. 

Tertian. 

1 1  days 

Tertian. 

Bein. 

Tertian. 

12  days 

Tertian. 

Bein. 

Tertian. 

12  days 

Tertian. 

Baccelli 

Tertian. 

6  days. 

Tertian. 

Mannaberg. 

Tertian. 

21  days. 

Tertian. 

Gualdi     and 

Anto- 

lisei. 

Quartan. 

io  days. 

Quartan. 

Gualdi     and 

Anto- 

lisei. 

Quartan. 

12  days. 

Quartan. 

Gualdi     and 

Anto- 

lisei. 

Quartan. 

1 5  days. 

Quartan. 

Di  Mattei. 

Quartan. 

1 8  days. 

Quartan. 

Di  Mattei. 

Quartan. 

1 1  days 

Quartan. 

Calandrucio 

Quartan. 

1 8  days. 

Quartan. 

Baccelli. 

Quartan. 

12  days. 

Quartan. 

Gerhardt. 

Aes.  autumn,  quotid. 

7  days. 

Aes.  autumn,  quotid. 

Gerhardt. 

Aes.  autumn,  quotid. 

12  days. 

Aes.  autumn,  quotid. 

Bignami. 

Aes.  autumn,  tertian. 

6  days. 

Aes.  autumn,  tertian. 

Bignami. 

Aes.  autumn,  tertian. 

io  days. 

Aes.  autumn,  tertian. 

Bastianelli  an 

d  Big- 

nami. 

Aes.  autumn,  tertian. 

3  days. 

Irregular  type. 

Bastianelli  an 

d  Big- 

nami. 

Aes.  autumn,  tertian. 

4  days. 

Irregular  type. 

Bastianelli  an 

d  Big- 

nami. 

•  Aes.  autumn,  tertian. 

5  days. 

Irregular  type. 

Bastianelli  and  Big- 

nami. 

Aes.  autumn,  tertian. 

4  days. 

Irregular  type. 

Panichi. 

Aes.  autumn,  tertian. 

5  days. 

Irregular  type. 

From  a  consideration  of  the  above  table  it  will  be  observed  that  the  in- 
cubation period  after  direct  inoculation  of  malarial  blood  varies  within  narrow 
limits  for  each  type  of  malaria,  the  longest  incubation  period  observed  being 
21  days  in  a  case  of  tertian  fever,  while  Elting  records  the  shortest  period  in 
aestivo-autumnal  fever,  the  symptoms  developing  33  hours  after  inoculation. 
While  the  period  of  incubation  observed  after  such  experiments  is  of  scientific 
interest  it  should  be  remembered  that  the  data  is  obtained  by  the  inoculation  of 
the  disease  in  an  unnatural  manner,  for  we  have  no  evidence  of  the  direct 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  117 

transmission  of  malaria  in  nature.  It  is  obvious  that  in  such  a  method  of 
transmission  only  the  forms  concerned  in  the  human  cycle  of  the  plasmodium 
undergo  development  and  therefore  that  we  can  draw  no  conclusions  regarding 
the  period  of  incubation  of  malaria  following  the  bite  of  infected  mosquitoes 
from  such  experiments.  Fortunately,  we  possess  data  concerning  the  period  of 
incubation  after  the  bite  of  infected  mosquitoes,  and  while  the  natural  period  of 
incubation  is  undoubtedly  very  variable,  it  is  probable  that  in  most  instances  it 
approximates  that  observed  in  experimental  cases  of  malaria  produced  by 
infected  insects. 

The  Incubation  Period  after  Experimental  Inoculation  by  the 
Mosquito. — In  the  inoculation  of  blood  containing  only  the  forms  of  the 
malarial  plasmodia  belonging  to  the  human  cycle,  it  is  reasonable  to  suppose 
that  the  period  of  incubation  will  be  shorter  than  that  observed  when  the 
mosquito  transmits  the  sporozoites  to  man.  That  this  is  so  has  been  proven 
experimentally  by  Marchiafava  and  Bignami,  Grassi,  Bastianelli,  Bignami, 
Manson,  Jancso,  and  other  observers. 

Marchiafava  and  Bignami  mention  one  instance  in  which  the  period  of 
incubation  after  the  bites  of  mosquitoes  infected  with  the  aestivo-autumnal 
plasmodia  was  from  nine  to  twelve  days,  and  one  in  which  the  period  of 
incubation  after  the  bites  of  mosquitoes  infected  with  the  tertian  plasmodium 
was  between  sixteen  and  nineteen  days.  Grassi,  Bignami,  and  Bastianelli 
report  a  case  in  which  the  incubation  of  aestivo-autumnal  fever  after  the  bite 
of  infected  mosquitoes  was  from  twelve  to  thirteen  days,  and  Bastianelli  and 
Bignami,  a  case  in  which  the  incubation  period  of  aestivo-autumnal  fever  was 
from  nine  to  twelve  days,  and  also  another  case  in  which  tertian  fever  developed 
in  18  days  after  the  bites  of  mosquitoes  infected  with  this  species  of  plasmodium. 
In  quartan  infections,  the  period  of  incubation  is  longer,  averaging  from  two 
to  nearly  three  weeks. 

From  these  observations  it  will  be  seen  that  the  period  of  incubation  of 
the  malarial  fevers  after  the  bites  of  infected  mosquitoes  varies  considerably 
according  to  the  type  of  infection,  but  is  always  longer  than  when  the  blood 
of  an  infected  individual  is  injected  directly  into  a  healthy  person.  The 
following  summary  well  illustrates  this  point: 

Incubation  after  Direct  Inoculation. — In  six  cases  of  tertian  fever, 
the  average  period  of  incubation  was  12  days. 

In  seven  cases  of  quartan  fever  the  average  period  of,  incubation  was 
13.5  days. 

In  nine  cases  of  aestivo-autumnal  infection  the  average  period  of  incuba- 
tion was  six  days. 

Incubation  after  Inoculation  by  the  Mosquito. — The  incubation  in 
tertian  fever  averages  14  days;  in  quartan  fever,  nearly  three  weeks;  in  aestivo- 
autumnal  infections,  10  to  12  days. 

Incubation  Period  after  Natural  Infection. — It  is  obvious  that  the 
period  of  incubation  after  natural  infection  is  generally  a  very  difficult  problem, 


Il8  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

and  can  only  be  determined  in  a  very  small  proportion  of  cases;  the  literature 
contains  very  scanty  information  upon  this  phase  of  our  subject,  the  most 
satisfactory  data  we  possess  being  furnished  by  Marchiafava  and  Bignami, 
Celli,  and  Jackson. 

Marchiafava  and  Bignami  were  so  fortunate  as  to  observe  three  cases  in 
which  they  could  be  sure  of  the  period  of  incubation.  These  cases  are  here 
given  in  the  words  of  the  authors: 

"CasE  I. — A  robust  young  man,  twenty- five  years  of  age,  living  in  the 
central  part  of  Rome,  had  never  had  malarial  fever.  On  November  4,  18Q4, 
he  was  obliged  to  go  to  Sermonetta,  a  notoriously  malarious  town  near  the 
Pontine  marshes.  He  arrived  in  the  city  at  10  o'clock,  slept  that  night,  tor- 
mented by  swarms  of  mosquitoes,  in  a  house  on  the  outskirts  of  Sermonetta, 
and  in  the  morning  returned  to  Rome,  where  he  resumed  his  usual  occupation. 
For  six  days  he  was  in  good  health,  then  he  had  two  days  of  malaise,  and  on 
November  13th,  that  is  to  say,  nine  days  after  his  stay  in  Sermonetta,  he  was 
taken  down  with  an  aestivo-autumnal  tertian  fever,  the  parasites  of  this  form 
being  found  in  the  blood. 

"Case  II. — An  engineer,  living  in  Rome,  who  had  never  suffered  from 
malaria,  was  constrained  by  the  duties  of  his  calling  to  pass  a  day,  in  October, 
1895,  in  a  place  in  the  Pontine  marshes,  and  he  slept  that  night  in  a  cabin  in  poor 
repair  in  which  were  many  mosquitoes.  At  the  end  of  ten  days  an  aestivo- 
autumnal  infection,  with  irregular  fever  developed,  of  which  he  had  several 
relapses,  extending  up  to  the  following  spring. 

"Case  III. — A  lady,  who  for  many  years,  had  enjoyed  good  health,  passed  a 
week  at  Fiumicino  in  the  month  of  October,  1894.  Three  days  after  her  return 
to  Rome  an  aestivo-autumnal  malarial  fever  declared  iself,  and  not  being'promptly 
treated,  developed  into  a  choleraic  pernicious  attack;  following  this  the  patient 
remained  profoundly  anaemic,  with  a  sanguinolent  diarrhoea,  and  died  at  the  end 
of  a  few  weeks." 

In  the  last  case  the  period  of  incubation  was  probably  from  nine  to  ten 
days. 

Jackson  gives  a  most  interesting  instance  in  which  a  limited  epidemic  of 
malaria  occurred  in  a  troop  of  United  States  Cavalry,  under  circumstances  in 
which  the  period  of  incubation  could  be  accurately  determined.  Out  of 
45  men  belonging  to  a  troop  of  the  6th  U.  S.  Cavalry,  exposed  at  the  same 
time  and  under  similar  conditions  to  infection,  18  developed  tertian  aestivo- 
autumnal  fever,  the  incubation  period  in  all  varying  between  ten  and  eleven 
days. 

In  two  cases  Zieman  noted  an  incubation  of  10  and  11  days  in  aestivo- 
autumnal  fever,  and  Navarre  describes  an  incubation  of  12  days  in  certain 
sailors  who  went  ashore  in  a  malarious  locality  for  three  hours  and  sailed 
immediately  afterward. 

It  will  be  observed  that  in  all  of  these  instances  the  period  of  incubation 
of  naturally  acquired  aestivo-autumnal  infections  agrees  exactly  with  the 
period  of  incubation  as  observed  in  cases  experimentally  produced  by  the 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  IIQ 

bites  of  infected  mosquitoes.  But  though  the  period  of  incubation  for  these 
infections,  as  well  as  for  tertian  and  quartan  infections,  in  the  vast  majority 
of  cases,  is  as  has  already  been  noted,  instances  do  occur  in  which  the  incubation 
is  greatly  prolonged.  Sternberg  quotes  the  instance  of  certain  sailors  who 
were  infected  while  their  ship  lay  for  two  days  in  a  malarious  port,  and  who 
developed  the  disease,  one  after  48,  the  other  after  184  days  after  leaving  the 
port.  The  following  instances,  observed  by  myself,  well  illustrate  the  variation 
in  the  length  of  the  period  of  incubation  in  the  malarial  fevers: 

In  August,  1899,  a  surgeon  of  the  United  States  Army  was  stationed  in  a 
malarious  locality  a  few  miles  from  Havana,  Cuba,  remaining  at  this  station 
until  September,  when  he  returned  to  New  York,  and  was  then  ordered  to 
San  Francisco.  While  at  the  station  in  Cuba  he  enjoyed  good  health  until 
a  day  or  two  before  leaving,  when  he  felt  somewhat  indisposed  but  no  definite 
symptoms  developed.  After  reaching  San  Francisco  he  remained  well  until 
March,  1900,  but  during  that  month  suffered  at  times  from  malaise  and 
diarrhea.  On  April  1st.  he  had  a  slight  chill  and  his  temperature  rose  to 
106. 20  F.  His  blood  showed  numerous  hyalin  and  pigmented  forms  of  the 
tertian  aestivo-autumnal  plasmodium,  and  though  this  attack  was  quickly 
overcome  by  quinine,  he  has  had  several  relapses. 

In  this  instance  it  is  undoubtedly  true  that  his  infection  occurred  in  Cuba, 
as  aestivo-autumnal  malaria  does  not  occur  in  either  New  York  or  San  Francisco 
and  he  was  in  no  other  places  than  these  after  leaving  Havana.  In  this  case, 
then,  the  incubation  period  was  at  least  seven  months.  It  is  probable  that 
had  he  remained  in  Cuba,  the  incubation  period  would  have  been  greatly 
shortened,  but  the  change  to  more  favorable  climatic  conditions  and  the 
consequent  benefit  to  his  general  health  delayed  the  onset  of  the  symptoms. 

In  another  instance  two  officers  of  the  Army,  stationed  at  a  malarious 
post  in  the  Philippines,  never  suffered  from  malaria  while  there,  but  one,  one 
month  after  returning  to  the  United  States,  developed  an  attack  of  tertian 
malaria,  while  the  other,  four  months  after  his  return,  developed  an  attack  of 
tertian  aestivo-autumnal  malaria.  Neither  of  these  officers  had  been  in 
malarious  regions  after  leaving  the  Philippines.  These  officers  were  both 
five  weeks  in  making  the  journey  from  the  Philippine  Islands  to  their  station 
in  the  United  States,  so  that  in  the  case  of  the  one  infected  with  tertian  fever, 
the  incubation  period  must  have  been  at  least  nine  weeks,  while  in  the  aestivo- 
autumnal  infection,  the  incubation  period  must  have  been  at  least  twenty-one 
weeks. 

I  might  give  many  more  instances  proving  that  the  incubation  period  in 
the  malarial  fevers  varies  very  greatly  at  times,  but  these  will  suffice.  The 
cause  of  this  variation  may  be  sought  in  the  number  of  sporozoites  inoculated  by 
the  mosquito,  the  resistance  of  the  individual  inoculated,  the  character  of  the 
sporozoites  as  regards  infectivity,  and  natural  conditions  favoring  the  develop- 
ment of  the  plasmodia  within  the  infected  individual.  Certain  it  is  that  in  a 
large  proportion  of  the  cases  presenting  long  periods  of  incubation,  the  theory 


120  THE    ETIOLOGY    OF    THE    MALARIAL   FEVERS. 

first  advocated  by  Thayer  is  true,  namely,  that  while  no  symptoms  are  pro- 
duced the  parasites  multiply  and  perform  their  life-cycle  in  small  numbers.  I 
am  the  more  convinced  of  this  as  it  is  borne  out  in  the  examinations  of  the  blood 
of  soldiers  returning  from  the  tropics.  While  serving  at  the  United  States 
Army  General  Hospital  at  the  Presidio,  I  examined  the  blood  of  every  case 
admitted  for  the  malarial  plasmodia,  without  regard  to  the  presence  of  symp- 
toms. This  routine  practice  led  to  the  surprising  discovery  that  nearly  40  per 
cent,  of  the  men  showing  malarial  parasites  in  their  blood  presented  no  symp- 
toms of  the  disease,  and  further  observations  embracing  1,297  cases  of  malaria 
in  Americans  have  shown  that  307,  or  nearly  24  per  cent.,  presented  parasites  in 
the  blood  but  no  symptoms  of  infection.  In  many  of  these  cases  I  have  observed 
the  plasmodia  for  days  and  even  weeks  in  small  numbers  in  the  peripheral 
blood,  and  in  tertian  and  quartan  infections  followed  the  normal  life-cycle  in 
man,  and  during  this  time  no  symptoms  of  malaria  have  developed.  It  is 
evident  that  the  long  period  of  incubation  in  such  cases  depends  upon  the  small 
number  of  the  plasmodia,  and  this  in  turn,  upon  the  resistance  of  the  individual. 
It  is  not  too  much  to  say  that  if  this  routine  practice  of  examining  the  blood  of 
every  individual  in  malarious  districts  or  of  those  coming  from  such  districts 
could  be  followed,  our  ideas  regarding  the  period  of  incubation  in  malaria  and 
the  relation  of  these  fevers  to  other  diseases  would  be  greatly  modified. 

The  question  arises,  How  long  may  a  susceptible  individual  live  in  a 
malarious  country  before  acquiring  the  disease  ?  It  is,  of  course,  impossible  to 
answer  this  question  for  all  cases;  but  in  the  great  majority  of  instances  a  suscep- 
tible individual  living  in  a  region  infected  with  the  tertian  or  aestivo-autumnal 
types  of  the  disease  will  acquire  the  fever  in  from  three  to  six  weeks,  while  it  is 
probable  that  quartan  infection  is  not  acquired  under  two  to  four  months. 
Marchoux  states  that  recruits  arriving  in  Senegal  develop  the  disease  in  from  14 
to  16  days  after  arrival  (aestivo-autumnal  fever)  and  of  the  hundreds  of  cases  of 
malaria  occurring  in  our  soldiers  in  Cuba  and  in  malarious  regions  in  the 
Philippines,  almost  95  per  cent,  of  those  whom  I  questioned  gave  a  history  of 
having  resided  in  these  countries  for  from  two  to  six  weeks  before  the  onset  of  the 
disease.  One  month  was  the  most  common  period  given  by  the  men  as  inter- 
vening between  landing  in  Cuba  and  the  first  chill,  and  the  same  is  true  of  cases 
observed  in  the  more  malarial  portions  of  the  Philippine  Islands. 

Congenital  Malaria. — For  many  years  it  was  believed  that  malaria  could 
be  transmitted  through  the  placenta  and  that  in  some  instances  babies  were 
already  infected  with  the  disease  at  birth.  Before  the  discovery  of  the  malarial 
plasmodia  this  theory  was  generally  accepted  and  served  to  explain  the  large 
infant  mortality  from  these  fevers  in  badly  infected  regions.  The  fact  that 
severe  malarial  attacks  were  capable  of  producing  abortion  or,  more  frequently 
miscarriage,  appeared  to  give  added  weight  to  the  placental  transmission  of 
these  fevers,  and  the  cases  reported  by  the  older  writers  upon  apparently  suffi- 
cient clinical  grounds,  led  many  observers  to  regard  this  method  of  transmission 
as  proven  and  of  great  practical  importance  in  malarial  countries.     The  dis- 


THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS.  121 

covery  of  the  malarial  plasmodia,  and  the  method  of  transmission  of  the  fevers 
produced  by  these  parasites,  rendered  most  of  the  evidence  in  favor  of  placental 
transmission  of  little  scientific  value,  as  none  of  the  cases  reported  had  been 
examined  as  to  the  presence  of  the  plasmodia  in  the  blood  or  tissues,  and  the 
large  infant  mortality  was  fully  accounted  for  by  the  facility  with  which  in- 
fected mosquitoes  bite  the  youngest  infants. 

A  few  of  the  older  reported  cases  deserve  some  credit,  however,  such,  for 
instance,  as  that  of  Duchek,  in  which  the  babe  showed  marked  splenic  enlarge- 
ment, and  at  autopsy,  three  hours  after  birth,  much  pigmentation  in  this 
organ  and  free  pigment  in  the  blood  of  the  portal  vein.  This  case  cannot  be 
considered  as  conclusive  since  similar  appearances  of  the  spleen  and  °f  the 
blood  might  be  produced  by  other  infections.  In  a  few  instances  malarial 
plasmodia  have  been  found  in  the  blood  of  newly-born  babes,  but  in  all  such 
instances  the  interval  elapsing  between  the  birth  of  the  children  and  the  exami- 
nation of  the  blood  has  been  sufficient  to  allow  of  postnatal  infection.  Such 
cases  have  been  reported  by  Bein,  Bouzian,  Peters,  and  a  few  other  observers. 

Opposed  to  the  inconclusive  evidence  offered  in  favor  of  congenital  malarial 
infection  we  have  the  observations  of  many  noted  students  of  this  disease  which 
prove,  I  believe,  that  the  malarial  fevers  cannot  be  transmitted  to  the  foetus 
through  the  placenta.  The  placental  blood  of  malarious  mothers,  the  blood  of 
infants  born  to  such  mothers,  and  the  blood  of  infants  whose  mothers  have 
aborted  by  reason  of  malarial  infection,  has  been  examined  by  many  competent 
investigators,  and  not  one  has  reported  the  presence  of  malarial  plasmodia  in 
such  blood  except  in  instances  in  which  infection  of  the  child  might  have  oc- 
curred after  birth.  Bignami  examined  the  blood  of  a  foetus  of  three  months 
and  of  another  of  six  months  from  women  who  had  aborted  because  of  perni- 
cious attacks  of  malaria,  with  a  negative  result  in  both  instances;  in  a  third  case, 
that  of  a  pregnant  woman,  who  died  of  pernicious  malarial  fever,  the  autopsy 
showed  the  lesions  usually  found  in  such  cases,  and  the  blood  contained 
multitudes  of  plasmodia,  but  the  blood  of  the  foetus  was  free  from  plasmodia, 
and  the  organs  showed  no  lesions  of  malarial  character.  Similar  cases  have 
been  reported  by  Bastianelli,  Caccini,  and  Schaudinn.  Bignami  has  demon- 
strated that  the  malarial  plasmodia  cannot  develop  within  the  nucleated  red 
blood-cells  of  the  foetus,  and  believes  that  this  is  also  true  as  regards  the 
young  red  corpuscles. 

In  an  elaborate  study  of  this  subject,  Sereni  concludes  that  placental  trans- 
mission of  the  malarial  plasmodia  is  impossible.  He  has  never  observed  the 
plasmodia  in  newly-born  children  of  malarial  mothers,  although  he  states  that 
the  placenta  contained  numerous  parasites.  Zieman,  in  Kamerum,  has  never 
observed  plasmodia  in  the  blood  of  newly-born  negroes,  although  in  four  cases 
the  mothers  were  suffering  from  malaria  at  the  time  of  giving  birth.  He  believes 
that  the  placenta  offers  an  impassable  barrier  to  the  plasmodia.  A  most 
interesting  case  reported  by  Thayer  supplies  conclusive  evidence  that  the 
transmission  of  malaria  through  the  placental  circulation  does  not  occur. 


122  THE    ETIOLOGY    OF    THE    MALARIAL    FEVERS. 

A  woman,  suffering  from  a  severe  quartan  infection,  gave  birth  to  a  seven 
months'  foetus  during  an  attack  of  the  fever.  The  blood  of  the  child  did  not 
show  any  plasmodia  nor  did  a  malarial  infection  develop  later,  but  an  examina- 
tion of  the  placenta  developed  the  interesting  and  significant  fact,  which  bears 
out  Zieman's  conclusion,  that  while  upon  the  maternal  side  numerous  plasmodia 
could  be  demonstrated,  there  was  a  complete  absence  of  them  upon  the  foetal 
side  of  the  organ.  '  From  the  evidence  at  hand  I  believe  that  we  are  justified  in 
stating  that  placental  infection  with  the  malarial  plasmodia  does  not  occur, 
and,  therefore,  that  congenital  malaria  does  not  exist. 

Literature    upon    Predisposing    Causes,    Period    of    Incubation,    and    Congenital 

Malaria. 

Predisposing  Causes  of  Malaria. 

For  the  literature  and  data  concerning  the  predisposing  causes  of  the  ma- 
larial fevers  consult  the  monographs  of  Marchiafava  and  Bignami,  Thayer, 
Mannaberg,  Zeiman,  Laveran  Celli,  and  Craig,  which  have  already  been  men- 
tioned. 

The   Incubation  Period   of  the   Malarial  Fevers. 

Consult  the  monographs  above  mentioned,  the  list  of  references  given  at 
the  end  of  Chapter  IV,  as  regards  the  period  of  incubation  after  direct  inocula- 
tion of  malarial  blood,  and  the  references  given  under  the  "Transmission  of  ma- 
laria by  the  Mosquito,"  for  the  work  of  Grassi,   Bastianelli,  and  Bignami. 
1899.      Elting.      Ueber  Malaria  nach  experimentellen  Impfungen.      Zeitschr.  f. 

klin.  Med.,  Bd.  36,  Nos.  5-6. 
1899.      Di    Mattel      Beitrag    zum    Studium    der    experimentellen    malarischen 

Infektion  am  Menchen  und  Tieren.     Archiv.  f.  Hyg.,  xxii,   No.  3,  p.  191. 
1 901.      Buchanan.      Experimental    Inoculation   of   Malarial   Fever   in    Nagpur. 

Indian  Med.  Gazette,  p.  127. 

1903.  Laveran.      Anopheles  et  Paludisme.      Comptes  Rendus.      April  6. 

1904.  Billet.      De  l'incubation  dans  le  paludisme.      Bull  med.  de  l'Algerie,  p. 
285-292. 

1904.  Mariotti-Bianchi.      II   periodo   l'incubazione   dell'    infezione    malarica. 
Atti  della  Societa  per  gli  Studi  della  Malaria,  vol.  v,  p.  81. 

1905.  Jackson.      Concerning   the   Invasion   Period   of   the    Malignant    (estivo- 
autumnal)  Tertian  Malarial  Parasite.      Am-  Med.,  vol.  viii,  67. 

Congenital  Malaria. 

1858.      Duchek.      Ueber    Intermittens.      Vierteljahrsschr.    f.    d.    prakt.    Helik. 

vol.  xi,   No.  60,  p.   73. 
1889.     Felkin.     Foetal   Malaria,    as   Illustrated  by  Two  Cases.      Edinb.  Med., 

Journ.,  June,  p.  1101. 
1894.      Bastianelli.      Sulla    transmissione     dei     parasiti    della    malaria    della 

madre  al  feto.      Bull,  della   Soc.   Lancisiana  degli  osped.   di   Roma,   xii, 

p.  48. 
1897.      Bignami.      Sulla   questione   della   malaria   congenita.      Supple,    al   Poli- 

clinico,  iv,  p.  763. 
1897.      Winslow.     A  Case  of  Congenital  Malaria.      Bost.  Med.  and  Surg.  Jour., 

MaY  27>  P-  5'4- 


THE    ETIOLOGY    OF    THE    MALARIAL   FEVERS.  1 23 

1902.  Peters,  L.      Malarial   Fever  in   Infancy,    Probably    Maternal  in   Origin. 
Johns  Hopkins  Hosp.  Bull.,  vol.  viii,  p.  139. 

1903.  Sereni.      Sulla  transmissibilita  dei  parassiti  della  malaria  della  madre 
al  feto.      Bull.  d.  R.  Accad.  di  Med.  di  Roma,  Fasc.  1-2-3. 

1906.  Zieman.      Article  upon  the  "Malarial  Fevers"  in  Menses  "  Handbuch  der 
Tropenkrankheiten. ' ' 

1907.  Thayer.      "  Malaria"  in  Allbut  and  Rolleston's  "System  of  Medicine," 
p.  247. 


PART  II. 

THE  GENERAL  AND  SPECIAL  PATHOLOGY  OF  THE 
MALARIAL  FEVERS. 


ALUMNI  ASSOCIATION, 

COLLEGE  OF  PHYSICIANS  AnDSU 
COLUMBIA  UNIVEkSU  Y 
NEW  YORK 

CHAPTER  I. 

The  General  Pathology  of  the  Malarial  Fevers;  Morphological  Changes  in 
the  Erythrocytes  and  Leucocytes;  Anaemia;  Differential  Blood  Count;  Phago- 
cytosis; Melanaemia;  The  Urine;  The  Etiology  of  the  Fever. 

Primarily,  malarial  infections  exert  the  most  marked  effect  upon  the  blood, 
as  the  plasmodia  live  at  the  expense  of  the  red  blood-corpuscles,  and  probably 
elaborate  toxins  which  materially  affect  all  of  the  elements  of  this  fluid. 
The  pathological  changes  which  occur  in  the  blood  as  the  result  of  malarial 
infections  are  due  to  primary  and  secondary  causes.  The  primary  cause  is  the 
infection  of  the  erythrocytes  with  the  plasmodia  and  the  changes  brought  about 
by  such  infection;  the  secondary  is  the  anaemic  condition  which  is  the  inevitable 
result  of  all  malarial  infection. 

Morphological  Changes  in  the  Erythrocytes  and  Leucocytes. — 
Certain  morphological  changes  occur  in  the  cells  of  the  blood  as  the  result 
of  the  invasion  of  the  red  corpuscles  by  the  plasmodia,  and  these  changes 
vary  with  the  species  of  plasmodia  concerned.  The  chief  changes  occurring 
in  the  erythrocytes  are: 

Changes  in  Size. — As  I  have  already  noted  the  red  blood-corpuscles 
when  invaded  by  Plasmodium  vivax,  the  tertian  parasite,  become  swollen,  and 
as  the  parasite  increases  in  size  the  red  corpuscles  also  enlarge  until,  when 
the  parasite  is  fully  developed,  the  red  cell  is  twice  or  three  times  as  large  as  the 
uninvaded  cells  surrounding  it.  t  This  is  a  characteristic  change  in  tertian 
infections.  In  cells  invaded  by  Plasmodium  malariae,  on  the  other  hand,  there 
is  no  increase  in  size,  but  the  invaded  red  cell  is  of  the  same  size  as  the  normal 
cells,  or,  in  a  few  instances,  somewhat  smaller.  In  infections  with  the  aestivo- 
autumnal  plasmodia,  the  invaded  red  cell  is  always  smaller  than  the  normal 
cells,  a  change  which  is  as  characteristic  of  these  infections  as  the  enlarged 
erythrocyte  is  of  tertian  malarial  infection. 

Changes  in  Form. — The  red  corpuscle  invaded  by  the  tertian  plasmodium 
is  generally  somewhat  distorted  in  shape  when  the  parasite  is  fully  grown, 
but  is  never  crenated.  In  quartan  infections  the  shape  of  the  red  cell  is  pre- 
served, as  it  generally  is  in  aestivo-autumnal  infections,  but  in  the  latter  crena- 
tion  of  the  cell  is  very  common,  especially  in  the  quotidian  aestivo-autumnal 
infections. 

Changes  in  Color. — In  tertian  infection  the  color  of  the  infected  red  cells 
is  much  paler  than  normal,  and  when  the  parasite  is  fully  developed  the  red 
cell  may  be  almost  colorless;  even  in  newly  invaded  cells  the  color  is  much  less 
marked  than  in  the  normal  red  corpuscles,  and  this  serves  as  a  diagnostic 

127 


128  THE    PATHOLOGY    OF    THE    MALARIAL    FEVERS. 

feature  in  differentiating  this  plasmodium  from  quartan  and  aestivo-autumnal 
organisms.  In  the  latter  infections  the  color  of  the  red  cell  invaded  by  the 
parasite  is  not  diminished,  but,  especially  in  the  aestivo-autumnal  infection, 
increases.  In  infections  with  the  quartan  parasite  the  color  of  the  infected  red 
cell  is  normal  or  else  it  is  slightly  more  greenish  than  normal;  in  the  aestivo- 
autumnal  infections  the  infected  red  cell  is  generally  darker  green  in  color  than 
normally,  and  may  appear  "brassy,"  the  cell  being  smaller  and  appearing 
shrivelled.  This  change  is  most  marked  after  a  paroxysm,  when  the  parasites 
have  become  pigmented,  and  the  dark  olive-green  color  of  the  invaded  cells  is 
generally  present  after  the  administration  of  quinine,  which  appears  capable  of 
producing  this  change  in  the  infected  corpuscles  in  both  aestivo-autumnal  and 
quartan  infections.  Marchiafava  and  Bignami  believe  that  the  "brassy" 
appearance  indicates  necrosis  of  the  red  cell  and  that  after  this  occurs  the  plas- 
modium within  the  cell  perishes.  I  believe  that  while  the  increase  in  color  may 
indicate  necrosis  of  the  red  cell,  this  necrosis  is  the  essential  result  of  its  invasion 
by  the  plasmodium,  and  that  the  latter  does  not  die,  but  undergoes  sporulation 
in  such  cells.  This  is  easily  demonstrated  in  smears  of  blood  from  the  spleen 
in  aestivo-autumnal  infections,  in  which  many  brassy  red  corpuscles  may  be 
seen  to  contain  sporulating  plasmodia.  The  "brassy"  cells  are  most  numerous 
in  quotidian  aestivo-autumnal  infections. 

Retraction  of  Haemoglobin  (  Partial  Decolorization  of  the 
Erythrocyte.) — Many  infected  red  corpuscles,  especially  in  aestivo-autumnal 
infections,  show  a  retraction  or  concentration  of  the  haemoglobin  at  some  por- 
of  tion  the  periphery  of  the  cell  or  within  it,  small  areas  being  colorless.  In  many 
instances  this  haemoglobin  membrane,  as  it  may  be  called,  is  retracted  about 
the  contained  parasite,  and  it  is  to  this  change  in  the  red  cell  that  the  "bib" 
and  double  outline  of  the  crescent  or  gamete  is  due.  In  malarial  infections  the 
uninvaded  red  cells  often  present  colorless  areas,  or  vacuoles,  which  are  many 
times  mistaken  for  hyaline  parasites  by  the  novice  in  blood  examinations,  and 
the  almost  colorless  center  of  anaemic  red  cells,  so  often  observed  in  malaria,  is 
not  infrequently  mistaken  for  a  plasmodium. 

Changes  in  the  Staining  Reactions  of  the  Erythrocytes. — In  ter- 
tian infections,  and  rarely  in  quartan  and  aestivo-autumnal  infections,  speci- 
mmens  of  blood  stained  by  one  of  the  modifications  of  Romanowsky's  method, 
show  reddish-stained  granules  in  the  protoplasm  of  the  invaded  red  cells,  known 
as  Schuffner's  dots.  I  have  already  spoken  of  the  diagnostic  significance  of  these 
dots  as  regards  tertian  infections  and  stated  that  this  change  in  the  staining 
reaction  of  the  red  cell  is  characteristic,  generally,  of  such  infections.  As  is  well 
known,  many  of  the  erythrocytes  in  severe  cases  of  malarial  infection  present 
the  phenomena  described  as  polychromasia  and  basophilic  degeneration.  This 
is  evidenced  by  areas  in  the  red  cell  or  the  whole  cell  staining  a  brownish  color  or 
the  cell  is  filled  with  granules  which  are  basophilic  in  character.  This  condition, 
however,  is  not  characteristic  of  malaria,  for  it  occurs  in  all  severe  anaemias  and 
in  many  other  diseases,  as  has  been  shown  by  many  observers,  notably  Maxi- 


THE  PATHOLOGY  OF  THE  MALARIAL  FEVERS.  1 29 

mow,  Askanazy,  Litter,  Bloch,  Fish,  Cabot,  Ewing,  Schwalbe  and  Solley, 
Grawisz,  and  Stengel,  White  and  Pepper. 

The  exact  nature  of  polychromasia  and  basophilia  is  as  yet  a  matter  of 
controversy,  some  authorities  regarding  the  process  as  degenerative  in  nature, 
while  others  maintain  that  it  is  not  of  necessity  a  regressive  process.  It  is 
not  advisable  here  to  consider  the  arguments  as  to  the  significance  of 
these  basic  staining  granules,  but  it  would  appear  that  so  far  as  the  study  of 
the  process  in  malaria  is  concerned,  the  evidence  all  points  to  its  degenerative 
nature. 

The  only  observations  regarding  the  significance  of  basophilia  of  special 
interest  to  the  student  of  malaria  are  those  of  A.  Plehn.  He  suggests  that  the 
granules  which  are  basophilic  in  character  and  which  are  observed  in  the  red 
cell  in  malaria,  are  in  reality  latent  forms  of  the  plasmodia.  He  believes  that 
multiplication  of  these  latent  forms  occurs  in  the  blood,  followed  by  destruction 
of  the  red  cells,  which  process  continues  until  conditions  are  favorable  for  the 
development  of  the  large  amoeboid  plasmodia.  He  also  states  that  after  the 
disappearance  of  the  amoeboid  forms  these  latent  bodies  remain,  continuing  as 
the  latent  form  of  the  plasmodium. 

The  observations  of  Plehn  have  not  been  confirmed  by  any  observer,  while, 
on  the  other  hand,  all  those  who  have  studied  the  subject  unite  in  considering 
the  basophilia  of  malaria  as  identical  with  that  occurring  in  other  diseases. 
Solly,  from  his  studies  of  tertian  malarial  blood,  found  granulations  of  the  red 
cell  in  only  two  out  of  thirty  cases,  and  concludes  that  there  is  no  evidence  that 
the  granulations  are  latent  malarial  plasmodia.  I  have  observed  basophilia 
in  a  very  great  number  of  specimens  of  malarial  blood,  and  agree  with  Solley 
that  there  is  no  evidence  whatever  that  the  granulations  are  a  form  of  the 
malarial  plasmodium.  To  believe  that  the  erythrocyte  contains  at  the  same 
time  a  growing  amoeboid  plasmodium  and  multitudes  of  latent  forms  (the 
dots)  is  impossible,  and  when  it  is  remembered  that  the  same  process  is  ob- 
served in  the  erythrocytes  in  other  diseases,  I  believe  that  Plehn's  hypothesis  is 
untenable,  and  unsupported  by  any  evidence  of  value.  No  morphological 
changes  of  importance  occur  in  the  leucocytes  in  malaria  with  the  excep- 
tion of  those  observed  in  phagocytosis,  which  will  be  discussed  later  in  this 
chapter. 

Malarial  Anaemia. — Every  malarial  infection,  whether  acute  or  chronic, 
is  accompanied  by  anaemia,  the  inevitable  result  of  the  destruction  of  the  red 
cells  by  the  invading  plasmodia,  and,  to  a  lesser  extent,  by  the  action  of  the 
toxins  liberated  in  the  blood  by  the  escape  of  the  parasites  from  the  red  cells. 
In  no  disease  is  the  destruction  of  the  red  corpuscles  more  rapid  than  in  malaria 
and  in  no  other  class  of  infections  is  anaemia  of  greater  diagnostic  importance, 
especially  if  it  has  appeared  suddenly  and  is  accompanied  by  chills  and  fever. 
The  anaemia  of  malaria  affects  both  the  red  and  white  corpuscles  and  the 
haemoglobin,  and  has  been  thoroughly  studied  by  nearly  every  writer  upon  these 
fevers,  but  to  Kelsch  we  owe  the  first  exhaustive  study  of  this  subject,  and  his 
9 


I30  THE    PATHOLOGY    OF    THE    MALARIAL    FEVERS. 

work,  completed  in  1876,  stands  to-day  almost  alone  in  its  thoroughness  and 
scientific  accuracy. 

The  Red  Corpuscles. — No  matter  how  slight  an  attack  of  malaria  we 
may  be  observing,  we  shall  invariably  find  a  reduction  in  the  number  of  red 
blood-corpuscles,  and  the  more  severe  the  attack  may  be  the  greater  will  be  the 
reduction  in.  these  cells.  In  severe  aestivo-autumnal  infections,  and  even  in 
tertian  and  quartan  infections  of  extraordinary  severity,  the  red  corpuscles  may 
fall  from  normal  to  3,000,000  per  cu.  mm.  within  48  hours,  and  in  pernicious 
attacks  the  reduction  may  be  even  greater.  Turk  describes  a  loss  of  1,000,000 
red  cells  in  one  day;  Mannaberg,  1,000,000  in  two  days,  and  Kelsch,  2,000,000 
in  two  days,  in  acute  aestivo-autumnal  infections.  I  have  observed  a  loss  of 
nearly  2,000,000  red  cells  in  thirty-six  hours  in  a  case  of  tertian  aestivo-autumnal 
malaria.  Marchiafava  and  Bignami  state  that  in  a  case  of  quotidian  malaria 
the  red  cells  were  reduced  1,000,000  within  24  hours,  and  Dionisi  found  that  in 
an  acute  attack  of  tertian  aestivo-autumnal  fever  which  had  lasted  three  days 
the  red  blood  count  showed  only  2,625,000  red  cells  per  cu.  mm.  In  pernicious 
attacks  of  aestivo-autumnal  malaria  Kelsch  states  that  in  one  day  the  red  cells 
may  be  reduced  to  1,000,000  per  cu.  mm.  in  initial  attacks,  while  if  the  patient 
has  already  suffered  from  malaria  and  is  thus  anaemic,  a  pernicious  attack 
generally  reduces  the  red  cells  to  from  1,000,000  to  2,000,000  per  cu.  mm.  In  a 
case  of  pernicious  quotidian  aestivo-autumnal  malaria,  which  proved  fatal,  I 
found  that  the  red  blood-corpuscles  only  numbered  860,000  per  cu.  mm.  a  few 
hours  before  death,  the  attack  having  lasted  about  five  days.  In  this  case  there 
was  no  rise  in  the  temperature  until  just  before  death,  so  that  the  anaemia  pro- 
duced was  not  dependent  upon  high  temperature. 

A  reduction  in  the  number  of  red  blood-corpuscles  follows  every  paroxysm 
for  a  certain  period  of  time,  but  it  will  always  be  observed  that  while  during 
the  first  few  days  of  an  initial  infection  the  reduction  is  marked,  the  continuance 
of  the  disease,  after  a  certain  amount  of  anaemia  has  been  produced,  is  not 
characterized  by  a  further  reduction,  but  the  number  tends  to  remain  at  a 
certain  level,  no  matter  how  long  the  infection  may  last.  In  each  recurrence 
it  will  be  found  that  the  reduction  in  the  number  of  red  corpuscles  is  less  and 
less  marked,  and  in  chronic  infections,  while  there  is  more  or  less  anaemia, 
there  is  but  a  slight  reduction  of  red  cells  after  a  paroxysm. 

The  return  to  the  normal  number  of  red  corpuscles  after  mild  or  even 
severe  attacks  of  tertian  and  quartan  fever  which  have  been  promptly  stopped 
by  treatment  is  usually  fairly  rapid,  but  cases  untreated,  or  in  which  many 
relapses  have  occurred,  are  followed  by  a  chronic  and  persistent  anaemia, 
which  is  one  of  the  most  marked  characteristics  of  people  inhabiting  malarial 
regions.  In  aestivo-autumnal  infections  the  return  to  the  normal  number  of 
red  cells  is  much  slower  than  in  tertian  and  quartan  infections,  and  after  a 
moderately  severe  attack  it  will  be  found  that  the  normal  number  of  red  cells 
is  not  reached,  as  a  rule,  before  the  end  of  two  months,  although  in  rare  instances 
recovery  is  rapid.     In  one  case  under  my  observation  the  red  cells  fell  to  690,000 


THE    PATHOLOGY    OF    THE    MALARIAL    FEVERS.  131 

per  cu.  mm.  in  three  days,  and  increased  to  2,100,000  per  cu.  mm.  in  three  weeks, 
after  treatment,  and  it  was  several  months  before  the  normal  number  of  red 
corpuscles  was  regained. 

Dionisi  has  contributed  some  very  valuable  data  concerning  the  anaemia 
of  the  aestivo-autumnal  infections  and  his  conclusions  are  here  given: 

"  1.  In  aestivo-autumnal  fever,  the  reduction  in  the  number  of  the  red  blood- 
corpuscles  bears  a  direct  relation  to  the  number  of  the  organisms.  Where  the 
parasites  are  numerous  there  is  a  constant  reduction  of  from  200,000  to  1,000,000 
with  each  febrile  paroxysm;  where  the  parasites  are  scanty  the  reduction  is  less. 

"2.  When  crescentic  bodies  are  present  in  addition  to  the  other  forms,  they 
seem  to  exert  no  influence  on  the  blood  changes. 

"3.  When,  after  a  paroxysm,  the  number  of  corpuscles  has  suffered  a  sud- 
den and  very  marked  diminution,  the  suceeding  paroxysms  may  be  followed  by 
but  a  slight  reduction  only,  or  even  by  an  increase. 

"4.  In  relapses,  the  reduction  per  paroxysm  is  less  than  in  a  primary  infec- 
tion. 

"5.  In  infections  determined  by  the  amoeboid  forms  (acute  aestivo-autum- 
nal infections)  there  is,  during  apyrexia,  no  complete  return  of  the  red  corpuscles 
to  their  normal  number.  Some  attempts  at  restitution  may  be  seen  during  the 
first  several  days  of  apyrexia,  while  after  this,  during  perhaps  eight  to  fifteen  days, 
there  may  be  a  steady  reduction  of  from  100,000  to  500,000  red  blood-corpuscles 
without  the  appearance  of  any  parasites  in  the  blood. 

"6.  Only  after  marked  and  continuous  reductions  following  each  paroxysm 
does  there  occur  in  the  afebrile  period  a  relative  restitution  of  the  red  blood-cor- 
puscles; this  may  be  slow  or  rapid. 

"7.  If  the  increase  in  the  corpuscles  has  begun,  the  presence  of  crescents 
has  no  deleterious  effect. 

"8.  In  tertian  and  quartan  fevers  the  same  changes  are  observed,  excepting 
that  in  the  afebrile  period  there  is  a  rapid  and  almost  complete  restitution  of 
the  red  blood-corpuscles." 

My  observations  upon  the  reduction  in  the  red  blood-corpuscles  in  aestivo- 
autumnal  fevers  confirm  those  of  Dionisi  in  all  essential  particulars,  but  I 
believe  that  the  reduction  observed  after  the  disappearance  of  the  symptoms, 
and  which  lasts  for  a  few  days,  is  due  to  plasmodia  whch  have  escaped  destruc- 
tion by  quinine,  which,  while  not  numerous  enough  to  produce  symptoms, 
destroy  a  certain  number  of  red  corpuscles.  This  may  also  serve  to  explain 
the  slow  restitution  of  the  red  blood-corpuscles  in  this  class  of  infections,  for, 
as  I  shall  demonstrate,  many  individuals  harbor  the  aestivo-autumnal  plas- 
modia for  weeks  without  presenting  any  definite  symptoms  of  malarial  infection. 

The  Leucocytes. — In  acute  malarial  infection  the  leucocytes  are  reduced 
in  number,  both  absolutely  and  relatively  to  the  red  blood-corpuscles.  Thus 
the  malarial  fevers,  like  typhoid,  dengue,  kala-azar,  and  trypanosomiasis,  are 
characterized,  as  a  rule,  by  a  marked  leucopenia,  only  the  pernicious  forms 
showing  a  leucocytosis.  During  the  first  hours  of  an  acute  attack  of  any  of 
the  forms  of  malaria  there  may  be  a  more  or  less  marked  leucocytosis,  some- 
times only  visible  during  the  first  fifteen  or  twenty  minutes,  at  others  still 


132  THE    PATHOLOGY    OF    THE    MALARIAL    FEVERS. 

demonstrable  until  the  decline  of  the  fever.  Generally  the  leucocytosis  is 
only  observable  for  a  short  time  at  the  onset  of  the  paroxysm,  soon  giving 
place  to  the  characteristic  leucopenia.  Kelsch  found  that  the  leucocytes 
gradually  decreased  in  number  as  the  paroxysm  continued  and  that  after  the 
attack  the  leucocytes  number  from  a  half  to  a  third  of  the  normal  number. 
After  recovery  the  leucocytes  increase  very  gradually  until  the  normal  number  is 
reached,  but  this  increase  is  very  slow  as  compared  to  the  rapidity  of  the  decrease 
during  the  active  stages  of  the  infection. 

In  tertian,  quartan,  and  in  ordinary  aestivo-autumnal  infections  the 
leucocytes  during  the  attack  number  from  3,000  to  5,000  per  cu.  mm.  as  a  rule, 
although  many  cases  are  observed  in  which  these  cells  number  from  2,000  to 
2,500  per  cu.  mm. 

In  the  pernicious  forms  of  malaria,  generally  due  to  the  aestivo-autumnal 
Plasmodia,  a  marked  leucocytosis  is  often  observed.  Kelsch  first  noted  this 
fact,  and  gives  instances  in  which  he  found  20,000,  25,000,  and  as  high  as 
35,000  leucocytes  per  cu.  mm.  I  have  never  observed  a  case  of  pernicious 
malaria  in  which  there  was  not  a  marked  leucocytosis,  and  in  one  instance,  due 
to  the  quotidian  plasmodium,  the  leucocytes  numbered  over  40,000  per  cu.  mm. 
When  recovery  occurs,  the  leucocytosis  quickly  disappears,  but  in  fatal  cases 
it  perists  to  the  end,  so  that  the  occurrence  of  a  marked  leucocytosis,  which 
tends  to  increase,  is  a  bad  prognostic  sign  in  pernicious  malaria. 

The  Differential  Leucocyte  Count. — Recently  much  attention  has  been 
paid  to  the  changes  occurring  in  the  relative  proportion  of  the  various  leucocytes 
in  acute  malarial  infections.  Rogers  called  attention  to  the  relative  increase 
in  the  mononuclear  leucocytes,  and  his  observations  have  been  confirmed  by 
numerous  investigators.  Stephens  and  Christophers  state  that  there  is  always 
an  increase  in  the  large  mononuclears,  and  they  consider  this  increase  of  great 
diagnostic  importance.  Billet  found  a  marked  increase  in  the  mononuclears 
and  considers  that  an  increase  in  the  polynuclears  indicates  a  complication. 
Poch,  in  his  studies  of  the  blood  in  tertian  and  quartan  infections,  found  a 
marked  initial  increase  in  the  polynuclears,  succeeded  by  an  increase  in  the 
mononuclears.  Zieman  describes  a  polynuclear  increase  at  the  beginning 
of  the  febrile  attack,  which,  at  the  height  of  the  fever,  disappears  rapidly, 
and  is  succeeded  by  a  relative  increase  in  the  large  mononuclears.  These 
changes  occur  in  initial  attacks  and  in  recurrences,  but  not  in  cachexia.  From 
my  own  observations,  I  believe  that  in  all  forms  of  malarial  infection,  during 
acute  attacks,  whether  initial  attacks  or  recurrences,  there  occurs  a  relative 
increase  in  the  mononuclear  leucocytes,  chiefly  the  large  mononuclears,  and 
that  this  increase  occurs  in  the  vast  majority  of  the  cases,  but  not  in  all.  An 
increase  in  the  polynuclear  leucocytes  is  often  observed  during  the  onset  of 
the  febrile  paroxysm,  especially  when  the  leucocytosis  is  marked,  but  a  poly- 
nuclear increase  occurring  during  the  subsidence  of  the  fever  or  in  the  apyrexial 
period  indicates  a  complication.  The  following  differential  blood  counts 
illustrate  those  commonly  obtained  in  malarial  infections: 


THE  PATHOLOGY  OF  THE  MALARIAL  FEVERS. 


J33 


Polynuclears, 
Small  mononuclears, 
Large  mononuclears 
and  transitionals, 
Eosinophiles, 

Polynuclears, 
Small  mononuclears, 
Large  mononuclears 
and  transitionals, 
Eosinophiles, 

Polynuclears, 
Small  mononuclears, 
Large  mononuclears 
and  transitionals, 
Eosinophiles, 


52 

.0%' 

16 

•3% 

32 

4% 

•3%) 

Count  in  tertian  malaria. 


55-°% 
20.6% 

22.2% 
3-°%  J 

45-°% 
18.4% 

5.o% 
35-6% 

1.0% 


Count  in  quartan  malaria. 


Count   in  aestivo-autumnal  infections. 


The  above  counts  are  intended  merely  to  illustrate  those  obtained  in 
malarial  disease  and  it  should  not  be  expected  that  all  counts  will  show  as  large 
an  increase  in  the  mononuclear  leucocytes,  although  in  the  majority  of  instances 
the  large  mononuclears  will  constitute  from  15  to  20  per  cent,  of  the  leucocytes 
observed.  The  greatest  increase  is  observed  during  apyrexia,  the  least  during 
the  height  of  the  fever.  The  differential  leucocyte  count  is  of  some  value  in 
differentiating  the  aestivo-autumnal  remittent  fevers  from  typhoid,  as  in  the 
latter  there  is  no  increase  in  the  large  mononuclear  cells,  although  there  is  a 
leucopenia  and  an  increase  in  the  small  mononuclears.  Rodgers  has  con- 
tributed several  valuable  studies  upon  the  diagnosis  of  malaria  and  typhoid  by 
means  of  the  differential  blood  count,  and  where  the  plasmodia  cannot  be 
found  or  the  Widal  test  applied  this  method  may  be  of  great  assistance  in  dif- 
ferential diagnosis.  It  is  of  but  little  value,  however,  in  differentiating  between 
malaria  and  such  diseases  as  kala-azar,  dengue,  or  trypanosomiasis,  as  in  the 
latter  a  large  mononuclear  increase  is  often  observed.  While  in  something 
over  50  per  cent,  of  cases  of  malarial  infection  a  relative  increase  in  the  large 
mononuclear  leucocytes  is  observed  it  has  not  been  my  experience  that  very 
much  weight  can  be  given  in  diagnosis  to  a  mononuclear  increase  in  malarial 
infection. 

The  Haemoglobin. — Besides  the  reduction  in  the  number  of  the  red  and 
white  blood-corpuscles,  there  is  generally  a  marked  reduction  in  the  haemo- 
globin in  all  malarial  infections,  but  especially  in  the  aestivo-autumnal  infections. 
This  reduction  is  usually  proportionate  to  the  loss  in  red  corpuscles,  but  in 
some  cases  the  haemoglobin  is  less  than  normal  in  proportion  to  the  loss  in 
the  red  corpuscles,  and  in  pernicious  cases,  the  loss  of  haemoglobin  may  be 
rapid  and  great,  from  10  to  40  per  cent,  being  lost  in  two  or  three  days.  How- 
ever, little  weight  can  be  given  to  the  reduction  in  haemoglobin  as  regards 
the  prognosis  of  individual  cases,  for  in  some  of  the  most  pernicious  forms 
of  malaria  that  I  have  observed,  there  has  been  but  a  slight  reduction  in  the 


134  THE    PATHOLOGY    OF    THE    MALARIAL    FEVERS. 

haemoglobin,  while  in  many  mild  tertian  infections  there  is  often  a  very  marked 
reduction. 

Rossoni  has  thoroughly  investigated  the  effect  of  malarial  infections  upon 
the  haemoglobin  index  of  the  blood  and  his  conclusions,  which  have  been 
confirmed  by  numerous  investigators,  are  as  follows: 

"i.  No  acute  -infection  results  in  as  active  a  deglobulization  as  does  ma- 
larial fever. 

"2.  In  all  cases  of  malarial  fever  there  is  an  immediate  diminution  in  the 
number  of  corpuscles  and  in  the  amount  of  haemoglobin.  This  loss  generally 
bears  a  direct  relation  to  the  duration  of  the  infection.  In  pernicious  cases, 
however,  a  diminution  of  as  much  as  two-thirds  of  the  total  amount  may  take 
place  in  from  one  to  three  days. 

"3.  The  gravity  of  pernicious  cases  does  not  always  bear  a  direct  relation 
to  the  extent  of  the  loss  in  haemoglobin. 

"4.  The  destruction  of  haemoglobin  and  corpuscles  bears,  generally,  a  direct 
relation  to  the  number  of  parasites  in  the  blood.  Occasionally,  however,  cases 
with  high  fever  and  marked  losses  in  haemoglobin  and  corpuscles  may  show  but 
few  parasites  in  the  circulating  blood.  A  long  continued  diminution  of  haemo. 
globin  is  often  associated  with  the  presence  of  crescents. 

"5.  The  loss  in  haemoglobin  and  corpuscles  is  rarely  evident  during  the 
paroxysm,  but  begins  with  apyrexia  and  may  continue  for  several  days  afterward. 

"6.  Recovery  from  malarial  anaemia  is  slower  than  from  the  other  acute 
anaemiae. 

"7  Usually  the  haemoglobin  and  corpuscles  are  equally  diminished,  but 
sometimes  the  haemoglobin  is  a  valuable  point  in  differential  diagnosis  between 
malarial   fever   and   enteric   fever   or   pneumonia. 

"8.  The  restitution  of  the  haemoglobin  in  malarial  anaemia  is  often  incom- 
plete, and  individuals  living  in  malarial  districts  have  often  a  slightly  smaller 
percentage  of  haemoglobin  than  those  living  elsewhere." 

Phagocytosis. — In  examining  the  blood  of  patients  suffering  from 
malarial  infections,  it  will  almost  invariably  be  noticed  that  many  of  the  leuco- 
cytes contain  brown  or  blackish  pigment,  portions  of  plasmodia,  or  even  whole 
plasmodia.  These  leucocytes  are  the  so-called  phagocytes  which  can  always 
be  demonstrated  in  malarial  blood  at  some  time  during  the  infection.  These 
pigment  containing  cells  were  observed  and  described  as  occurring  in  the  blood 
before  the  plasmodia  of  malaria  were  discovered,  and  Laveran,  Marchiafava, 
Celli,  Golgi,  Metchnikoff,  Bignami,  Osier,  Barker,  Dock,  and  Thayer  have 
all  added  to  our  knowledge  of  these  cells.  In  the  tertian  and  quartan  infections 
phagocytes  were  observed  to  be  most  numerous  during  or  just  after  the  par- 
oxysms, while  in  the  aestivo-autumnal  infections  these  cells  appeared  at  less 
regular  intervals.  Marchiafava  and  Celli  first  proved  that  the  phagocytes 
are  capable  of  engufilng  and  destroying  living  plasmodia,  Laveran  having  held 
that  the  pigment  observed  in  these  cells  was  engulfed  only  after  the  fragmenta- 
tion and  death  of  the  plasmodia.  That  Marchiafava  and  Celli  were  right  in 
their  observations  may  be  proven  by  any  one  interested,  for  one  of  the  most 
interesting  and  instructive  phenomena  visible  under  the  microscope,  is  the 
engulfing  of  extracellular  malarial  plasmodia  by  the  phagocytic  leucocytes. 


THE    PATHOLOGY    OF    THE    MALARIAL    FEVERS.  135 

Golgi,  as  the  result  of  his  researches  upon  phagocytosis  in  tertian  and 
quartan  malaria,  and  Marchiafava,  Bignami,  and  Bastianelli,  as  the  result  of 
theirs  in  aestivo-autumnal  fevers,  have  demonstrated  that  phagocytosis  occurs 
most  commonly  during  the  early  hours  of  a  malarial  attack,  and  that  during 
apyrexia  this  process  almost  disappears.  Golgi  considered  that  to  phagocytosis 
we  owe  spontaneous  recovery  in  malaria,  and  his  opinion  agrees  with  that  of 
Metchnikoff,  who  believes  that  these  cells,  either  by  engulfing  and  digesting 
the  plasmodia  or  by  excreting  products  inimical  to  their  growth,  bring  about 
recovery  in  most  cases  of  malarial  infection. 

The  Phagocytic  Cells. — The  cells  which  act  as  phagocytes  in  malaria  are: 
the  large  mononuclear  and  transitional  leucocytes,  as  well  as  certain  of  the 
polynuclear  cells;  the  endothelium  of  the  liver  and  Kupffer's  cells;  the  cells  of 
the  splenic  pulp,  and  the  uninuclear  leucocytes  in  the  bone  marrow.  The 
small  mononuclears  and  the  eosinophiles  have  been  said,  by  some  observers, 
to  be  phagocytic,  but  these  cells  are  not  generally  so.  In  one  or  two  instances, 
I  have  observed  entire  plasmodia  within  coarsely  granular  eosinophiles,  so 
it  is  impossible  to  deny  that,  under  certain  conditions,  these  cells  may  become 
phagocytic,  but  they  are  not  so  normally. 

The  large  mononuclears  and  the  transitionals  in  the  peripheral  blood,  and 
to  a  lesser  degree  the  polynuclears,  are  the  chief  phagocytic  agents  in  all 
malarial  infections,  and  while  the  total  number  of  leucocytes  in  these  infections 
is  decreased,  it  will  be  noted  that  the  phagocytic  cells  are  relatively  increased, 
thus  adding  support  to  Metchnikoff 's  theory  that  to  these  cells  we  owe  sponta- 
neous recovery  in  malaria. 

The  endothelial  cells  of  the  liver  are  found  in  the  peripheral  circulation 
acting  as  phagocytes  in  only  the  most  pernicious  cases  of  malaria,  but  in  the 
liver  these  cells,  as  well  as  the  cells  of  Kupfer,  are  actively  phagocytic,  show- 
ing within  them  pigment,  plasmodia,  and  even  red  blood-cells  containing  the 
plasmodia.  In  fatal  cases,  these  cells  are  often  observed  lying  free  in  the 
capillaries,  crowded  with  pigment  and  parasites,  and  even  those  cells  still 
attached  to  the  vessel  walls  contain  much  pigment  and  fragments  of 
plasmodia. 

The  cells  of  the  splenic  pulp  are  very  actively  phagocytic  and  here  we  find 
immense  cells,  from  10  to  20  times  the  size  of  the  small  mononuclear,  containing 
great  blocks  of  pigment,  plasmodia  in  various  stages  of  development,  and 
even  entire  infected  red  blood-corpuscles.  These  large  cells  are  known  as 
macrophages,  and  are  characteristic  of  malarial  infection.  The  splenic  vessels, 
in  fatal  cases  of  malaria,  are  crowded  with  these  macrophagi,  with  free  malarial 
pigment,  and  degenerated  cellular  material,  and,  as  Marchiafava  and  Bignami 
suggest,  it  is  probable  that  many  of  the  melaniferous  cells  observed  in  the 
vessels  of  the  liver  are  really  derived  from  the  splenic  pulp. 

Degenerative  Changes  in  the  Phagocytic  Cells. — In  pernicious  cases 
of  malaria  there  occur  in  the  peripheral  blood  numerous  phagocytic  cells 
which  are  evidently  undergoing  degeneration,  and  sections  of  the  liver,  the 


I36  THE    PATHOLOGY    OF    THE    MALARIAL    LEVERS. 

spleen,  and  smears  of  the  bone  marrow,  in  such  cases,  show  numerous  degenera- 
ing  phagocytes.  The  forms  of  degeneration  occurring  in  these  cells  comprise 
vacuolization,  fatty  degneration,  and  fragmentation  of  the  nucleus.  Such 
forms  of  degeneration  occur  rarely  in  leucocytes  which  present  no  evidence  of 
phagocytosis.  The  degenerative  changes  are  most  common  and  marked  in 
the  large  mononuclear  leucocytes  and  in  the  macrophages.  Bignami  has  claimed 
that  the  malarial  spores  are  capable  of  developing  after  the  necrosis  of  the 
phagocyte  which  has  engulfed  them,  but  his  theory  has  never  been  proven  and 
it  is  extremely  doubtful  whether  any  form  of  the  malarial  plasmodia  is  capable 
of  development  after  it  has  once  been  engulfed  and  acted  upon  by  the  phagocytic 
cell. 

Time  of  Occurrence  of  Phagocytosis. — In  tertian  and  quartan  malarial 
fevers  phagocytosis  is  most  marked  during  or  directly  after  the  chill,  and  this  is 
true  also  in  uncomplicated  cases  of  tertian  and  quotidian  aestivo-autumnal 
malaria  during  an  acute  attack.  If,  however,  the  disease  has  persisted  for 
some  time  or  there  is  a  double  infection,  the  cyclical  appearance  of  phagocyto- 
sis cannot  be  demonstrated  without  repeated  observations  and  most  careful 
study,  and  often  not  even  then.  In  pernicious  cases  phagocytes  are,  as  a  rule, 
very  numerous,  especially  the  large  mononuclear  variety,  and  the  macrophages. 
Quinine  tends  to  increase  phagocytosis,  especially  in  pernicious  cases.  In 
many  instances  of  severe  aestivo-autumnal  infection  an  examination  of  the 
blood  at  any  time  will  show  a  marked  phagocytosis,  due  in  all  probability  to 
the  rapid  and  irregular  multiplication  of  the  plasmodia. 

Substances  Engulfed  by  the  Phagocytes. — In  malarial  infections  the 
following  are  found  within  phagocytic  cells:  first  and  most  common,  free  pig- 
ment; second,  extracellular  plasmcdia,  many  of  which  are  flagellated;  third, 
shrunken  and  degenerated  red  corpuscles,  both  with  and  without  parasites 
(these  occur  only  within  macrophages) ;  fourth,  segmenting  plasmodia  (common 
in  blood  from  the  spleen);  fifth,  crescentic  and  ovoid  forms  (very  rarely).  The 
amount  of  pigment  and  cellular  detritus  absorbed  by  the  phagocytes  is  enor- 
mous, and  there  can  be  no  doubt  that  these  cells  are  of  inestimable  value  to  the 
organism  in  taking  from  the  capillaries  and  small  vessels  this  material  which 
might  so  easily  occlude  them.  In  this  way  alone  phagocytosis  in  malaria  is  of 
the  very  greatest  importance,  for  without  it  we  would  observe  pernicious 
symptoms  in  the  majority  of  our  cases. 

The  Significance  of  Phagocytosis. — The  fact  that  the  phagocytes  not 
only  engulf  and  clear  the  vessels  of  pigment  and  cellular  deteritus,  but  that 
they  can,  and  do,  engulf  and  destroy  large  numbers  of  living  plasmodia  proves 
that  this  process  must  be  one  of  vital  significance.  It  is  undoubtedly  true  that 
the  sporulation  of  the  plasmodia  acts  as  the  stimulating  factor  to  phagocytosis, 
for,  as  I  have  shown,  this  process  is  most  marked  during  a  malarial  paroxysm, 
and  this  fact  would  appear  to  indicate  that  phagocytosis  is  an  important,  if  not 
the  most  important,  means  of  defense  possessed  by  the  organism  against 
malarial  infection.     Two  theories  have  been  advanced  regarding  the  signifi- 


THE    PATHOLOGY    OF    THE    MALARIAL    FEVERS.  137 

cance  of  this  process,  one,  advocated  by  Metchnikoff  and  his  followers,  that 
phagocytosis  in  malaria  is  an  active  protective  process  and  is  the  cause  of 
spontaneous  recovery;  the  other,  advocated  by  Bastianelli,  that  it  has  but  little 
to  do  with  spontaneous  recovery,  and  that  the  facts  are  not  sufficient  to  prove 
that  the  phagocyte  is,  as  Metchnikoff  believes,  an  active  enemy  of  the  malarial 
plasmodia. 

We  believe  that  there  can  be  no  doubt  in  the  mind  of  a  careful  observer 
that  the  phagocytic  cells  perform  a  very  active  part  in  the  destruction  of  living 
malarial  plasmodia,  and  that,  therefore,  the  phagocyte  is  an  active  enemy  of 
these  organisms.  We  believe  that  it  is  also  clear  that  this  process  exercises 
an  important  mission  in  enabling  the  organism  to  recover  from  the  infection, 
but  we  doubt  that  phagocytosis  is  the  direct  and  only  cause  of  spontaneous 
recovery.  The  immense  value  of  the  process  in  ridding  the  vessels  of  the  viscera 
the  bone  marrow,  and  the  peripheral  capillaries  of  free  pigment,  cellular 
detritus,  and  degenerated  plasmodia  must  be  admitted,  for  after  pernicious 
attacks  of  malaria,  only  a  few  days  supervene  before  the  body  is  practically 
cleansed  of  the  results  of  the  infection,  such  as  pigment,  degenerated  red  cells 
and  leucocytes,  and  fragmented  and  moribund  plasmodia. 

In  many  malarial  infections,  especially  the  aestivo-autumnal  fevers, 
phagocytosis  has  considerable  prognostic  value.  From  my  own  observations 
I  would  say  that  the  following  rule  will  hold  true  in  almost  every  case  of  aestivo- 
autumnal  malaria:  The  greater  the  phagocytosis  the  more  severe  is  the  in- 
fection and  the  more  grave  the  prognosis.  Especially  is  this  true  if  in  the  per- 
ipheral blood  occur  numerous  large  mononuclear  phagocytes  or  macrophages. 
I  am  convinced  that  a  marked  phagocytosis  in  aestivo-autumnal  malaria,  far 
from  being  a  feavorable  sign,  is  almost  typical  of  a  pernicious  infection,  and  if  no 
cyclical  course  can  be  traced  after  repeated  examinations,  is  absolutely  typical, 
and  should  be  the  signal  for  the  institution  of  the  most  energetic  therapeutic 
measures. 

It  would  appear,  from  the  evidence  at  hand,  that  phagocytosis  is  one  of  the 
weapons  possessed  by  the  organism  which  enable  it  to  overcome  malarial  in- 
fection, both  by  the  property  possessed  by  the  phagocyte  of  engulfing  and 
destroying  the  living  plasmodia,  and  by  removing  from  the  organism  the  pig- 
ment and  cellular  detritus  which  would  otherwise  accumulate  and  injure  the 
tissues.  This  process  cannot  be  considered  as  the  cause  of  spontaneous  re- 
covery, acting  alone,  but  it  is  one  of  the  most  important  factors  concerned  in 
such  recovery,  and  may  be  the  principal  factor  in  many  instances.  It  is  cer- 
tainly true  that  Metchnikoff  is  correct  in  considering  the  phagocyte  as  an  active 
agent  in  ridding  the  body  of  malarial  plasmodia,  and  it  may  well  be  that  in  the 
phagocyte  we  have  the  true  explanation  of  malarial  immunity. 

Melanaemia. — The  occurrence  within  the  blood  of  malarial  pigment, 
either  free  or  enclosed  within  the  leucocytes,  is  known  as  melanaemia,  and,  next 
to  the  occurrence  of  the  plasmodia  within  the  red  corpuscles,  is  the  most  char- 
acteristic change  occurring  in  the  blood    n  malarial  infections,  and  is  the  one 


130  THE    PATHOLOGY    OF    THE    MALARIAL    FEVERS. 

which  has  been  longest  known  to  the  students  of  these  fevers.  This  pigment 
may  be  brown,  brownish-yellow,  or  black  in  color,  and  may  occur  in  the  form  of 
blocks,  granules,  rods,  grains,  irregular  clumps,  fine  needles,  or  cylindrical, 
polyhedral,  circular  or  irregular  masses.  This  condition  is  only  present  in 
malarial  infections,  and  is  often  of  great  service  in  diagnosis  where  the  parasites 
are  few  in  number  or  in  chronic  malarial  poisoning. 

Historical. — The  history  of  the  discovery  and  explanation  of  pigment  in 
the  blood  in  malaria  is  of  interest,  but  we  can  only  touch  upon  it  in  this  con- 
tribution. Meckel,  in  1847,  was  the  first  to  describe  pigment  as  occurring  in 
the  blood  in  malaria,  and  his  observations  were  soon  confirmed  by  those  of 
Virchow  and  Frerichs,  and  these  authorities  considered  that  the  pigment  was 
derived  from  the  spleen  or  liver,  although  Frerichs  believed  that  it  origi- 
nated in  the  spleen  alone,  being  due  to  the  destruction  of  the  blood  in  that 
organ.  Meigs  and  Colin  wrote  excellent  descriptions  of  this  condition,  but 
to  Arnstein  we  owe  the  discovery  that  the  pigment  originates  in  the  circulating 
blood  during  the  malarial  paroxysm,  being  deposited  afterward  in  the  liver, 
spleen,  bone  marrow,  and  other  viscera.  He,  together  with  Kelsch,  came  to  the 
conclusion  that  the  destruction  of  the  red  blood-cells  in  malaria  gave  rise  to  the 
pigment,  which  remained  in  solution  in  the  blood  until  the  latter  became 
saturated,  when  it  was  precipitated  in  granules  which  were  then  engulfed  by  the 
leucocytes.  This  theory  was  accepted  until  the  investigations  of  Laveran, 
Marchiafava,  and  Celli,  who  demonstrated  that  the  pigment  is  not  formed 
after  the  disintegration  of  the  red  corpuscles,  but  is  formed  during  the  growth 
of  the  malarial  plasmodia  within  them,  being,  in  fact,  the  changed  hemoglobin 
of  the  corpuscles  absorbed  by  the  plasmodia  during  their  growth.  The  true 
malarial  pigment,  or  melanin,  is  elaborated  during  the  development  of  the 
plasmodia  within  the  infected  cell  and  is  liberated  when  sporulation  of  the 
parasites  occurs. 

Varieties  of  Pigment. — Two  varieties  of  pigment  are  present  in  the 
blood  in  malarial  infections:  one,  melanin,  the  true  malarial  pigment,  is  black  in 
color,  and  is  found  in  both  the  blood  and  tissues;  the  other,  haemosiderin,  is 
yellow  in  color,  and  is  found  only  in  the  tissues.  The  first  gives  no  reaction  for 
iron;  the  second  does. 

As  regards  the  origin  of  the  two  varieties,  I  am  fully  in  accord  with  Big- 
nami,  who  says:  "The  melanaemia,  index  of  an  acute  infection,  is  derived 
only  from  the  direct  transformation  of  haemoglobin  into  melanin  through  the 
action  of  the  parasites  within  the  red  corpuscles,  as  Marchiafava  and  Celli  have 
demonstrated;  that  the  melanosis  of  the  viscera,  spleen,  liver,  bone-marrow,  etc., 
index  of  a  previous  infection,  has  a  double  origin.  In  chief  part  it  is  derived 
from  the  melanaemia,  that  is,  from  the  deposition  in  the  viscera  of  the  black 
pigment  formed  during  the  acute  infection  in  the  circulating  blood;  in  part  it  has 
a  local  origin,  that  is,  it  is  derived  from  the  slow  transformation  of  the  blocks  of 
ochre-colored  pigment  which  are  deposited  or  formed  in  the  spleen  and  in  the 
other  viscera  from  the  enormous  quantity  of  altered  red  blood-corpuscles, 


THE    PATHOLOGY    OF    THE    MALARIAL    FEVERS.  I39 

which,  in  grave  infections,  die  before  the  direct  action  of  the  parasites  has 
transformed  their  haemoglobin  into  black  pigment." 

Chemical  Characteristics  of  Melanin  and  Haemosiderin. — Melanin 
(the  black  pigment)  is  not  acted  upon  by  strong  acids,  but  is  decolorized  by  the 
potassium  and  ammonium  salts;  it  is  very  soluble  in  sulphide  of  ammonium,  but 
insoluble  in  strong  acids.  No  trace  of  iron  has  ever  been  demonstrated  in 
melanin,  but  this  fact  does  not  prove  that  it  is  not  present.  In  all  probability, 
melanin  is  closely  allied  to  haematin,  as  is  held  by  Carbone,  who  believes  that  it 
is  identical  with  the  latter. 

Haemosiderin  (the  yellow  pigment)  is  insoluble  in  strong  acids,  caustic 
potash,  alcohol  and  water;  turns  black  when  treated  with  sulphide  of  am- 
monium, and  gives  a  blue  color  when  treated  with  ferrocyanide  of  potassium 
and  hydrochloric  acid.  Thus  it  will  be  seen  that  this  pigment,  unlike  melanin, 
gives  an  iron  reaction. 

Distribution  of  Melanin  and  Haemosiderin. — Melanin  occurs  in  the 
blood  and  tissues  in  the  form  of  minute  granules  of  a  dark  brown  or  nearly 
black  color,  which  tend  to  accumulate  in  small  irregular  clumps  when  situated 
in  the  viscera.  In  tertian  infections  the  melanin  is  generally  of  a  golden-brown 
color,  while  in  quartan  and  aestivo-autumnal  infections  it  is  darker,  generally 
almost  black.  This  pigment,  formed,  as  has  been  said,  within  the  red  cells  or, 
more  properly,  within  the  body  of  the  plasmodium,  is  liberated  with  the  seg- 
ments during  sporulation,  and  is  taken  up  by  the  leucocytes  or  is  deposited  in 
certain  tissues,  especially  in  the  brain,  spleen,  liver,  and  bone-marrow.  This 
pigment  is  engulfed  by  the  large  mononuclear  leucocytes,  the  polynuclear 
leucocytes,  and  rarely  by  the  eosinophiles,  but  not  by  the  endothelial  cells  of 
the  liver  and  spleen,  or  by  Kupfer's  cells  in  the  liver.  In  the  tissues  this  pig- 
ment may  often  be  seen  in  large  quantities,  much  of  it  having  reached  this 
locality  by  diapedesis  of  leucocytes  containing  the  pigment  or  by  the  rupture  of 
capillary  vessels  which  have  become  occluded  by  phagocytic  leucocytes  and 
masses  of  melanin.  This  pigment  occurs  free  in  the  blood  plasma,  but,  while 
used  as  a  diagnostic  evidence  of  malarial  infection,  such  free  pigment  cannot  be 
relied  upon  in  diagnosis,  as  extraneous  particles  of  dirt,  so  common  in  blood 
specimens,  cannot  be  differentiated  morphologically  from  melanin.  Pigmented 
leucocytes,  provided  the  pigment  contained  within  them  is  dark  brown  or  black 
in  color,  are  of  value  in  diagnosis.  In  pernicious  malaria  melanin  occurs  in 
considerable  amount  in  the  kidneys  and  the  lungs,  as  well  as  the  muscular  wall 
of  the  heart,  and  in  cases  characterized  by  intestinal  irritation  this  pigment  is 
common  in  the  villi  of  the  intestine. 

The  yellow  pigment,  or  haemosiderin,  occurs  within  the  tissues,  never  in 
the  peripheral  blood.  In  the  liver  and  spleen,  and  in  smaller  quantity  in  the 
bone-marrow,  kidneys,  and  other  viscera,  this  pigment  occurs  in  the  form  of 
fine  grains,  larger  masses  of  an  amber  color,  and  large  blocks  or  masses  of  a 
golden-yellow  color.  It  is  especially  abundant  in  fatal  cases  of  pernicious 
aestivo-autumnal  fevers,  occurring  in  such  cases  chiefly  in  the  liver  and  spleen. 


1 4°  THE    PATHOLOGY    OF    THE    MALARIAL    FEVERS. 

This  pigment  is  also  derived  from  the  haemoglobin  of  the  red  corpuscles,  but 
from  corpuscles  which  have  not  been  invaded  by  the  plasmodia.  Unlike 
melanin,  this  pigment  is  observed  within  the  endothelial  cells  of  the  viscera  and 
in  Kupfer's  cells,  as  well  as  in  the  cells  of  the  spleen  and  within  the  epithelium 
of  the  kidney  tubules.  Melanin  occurs  chiefly  in  the  phagocytic  cells  in  the 
capillaries  of  the  viscera,  while  haemosiderin  occurs  most  frequently  within  the 
tissue  cells  of  the  viscera. 

There  is  some  evidence  which  goes  to  prove  that  melanin  may  be  derived 
from  haemosiderin,  under  certain  conditions,  and  Bignami  believes  that  this 
change  occurs  after  the  acute  infection  in  haemosiderin  formed  during  the 
paroxysms  of  the  fever. 

Summary  of  Blood  Changes. — Summing  up  our  knowledge  as  regards 
the  changes  in  the  blood  in  the  malarial  fevers,  it  may  be  briefly  stated  as  fol- 
lows: A  marked  reduction  in  the  number  of  red  corpuscles,  both  by  parasitic 
invasion  and  as  the  result  of  poisons  elaborated  by  the  plasmodia  during  their 
development,  as  well  as  changes  brought  about  in  the  blood-forming  glands  by 
the  malarial  infection;  a  corresponding  reduction  in  the  number  of  white  cells, 
with,  in  most  cases,  a  relative  increase  in  the  large  mononuclear  leucocytes;  a 
marked  reduction  in  the  haemoglobin,  and  the  presence  in  the  blood  of  black 
and  brownish-yellow  pigment,  in  greater  or  lesser  amount. 

The  Urine  in  Malarial  Infections. — In  most  malarial  infections  the  urine 
shows  some  departure  from  the  normal,  and  in  aestivo-autumnal  infections,  and 
the  more  severe  tertian  and  quartan  infections,  very  grave  pathological  condi- 
tions may  be  present.  A  number  of  observers  have  studied  the  urine  in  malaria 
and  have  described  the  conditions  present,  notably  Rem-Picci,  Thayer,  Celli, 
and  Botazzi  and  Pensuti. 

Quantity. — In  tertian  and  quartan  infections  the  amount  of  urine  passed 
in  24  hours  is  generally  increased,  while  in  aestivo-autumnal  infections  the 
quantity  is  normal  or  decreased.  In  certain  cases  of  aestivo-autumnal  infection 
the  quantity  is  greatly  increased.  During  the  malarial  paroxysm  a  large 
amount  of  urine  is  often  passed,  due  to  the  increased  vascular  tension  present 
during  the  cold  stage;  the  smallest  amount  of  urine  passed  is  generally  during 
the  interval  between  the  paroxysms. 

Polyuria  is  not  infrequently  observed  during  convalescence  from  all  malarial 
infections,  but  especially  in  the  convalescence  of  tertian  and  quartan  cases. 
Rem-Picci  observed  it  in  60  of  150  cases,  and  I  would  even  put  the  percentage 
higher,  as  I  have  found  it  present  in  at  least  80  per  cent,  of  all  cases  in  which 
special  attention  was  paid  to  the  urine.  Polyuria,  however,  is  not  confined  to 
the  stage  of  convalescence,  for  it  is  observed  during  the  attacks  or  immediately 
following  each  paroxysm  of  the  fever.  It  may  last  a  few  days  or  several  weeks. 
I  observed  an  interesting  case  in  which  the  patient  recognized  the  impending 
occurrence  of  a  malarial  paroxysm  by  the  greatly  increased  amount  of  urine  he 
passed  just  before  the  onset  of  the  chill.  The  daily  amount  of  urine  passed 
when  polyuria  is  present  averages  from  two  to  three  liters,  but  may  be  much 


THE    PATHOLOGY    OF    THE    MALARIAL    FEVERS.  141 

greater.  One  patient  under  my  observation,  after  a  tertian  aestivo-autumnal 
attack,  passed  from  20,000  to  25,000  c.c.  of  urine  per  day,  for  several  weeks. 
This  is  a  very  unusual  occurrence,  however,  especially  in  aestivo-autumnal 
infections,  in  which  polyuria  is  not  as  common  as  in  tertian  and  quartan 
infections. 

Specific  Gravity. — During  the  attack  the  specific  gravity  is  increased, 
although  the  amount  of  urine  passed  may  be  excessive.  After  the  attack, 
the  specific  gravity  is  generally  normal,  unless  polyuria  be  present,  when  it 
varies  with  the  amount  excreted,  but  is  generally  low.  In  cases  presenting 
polyuria  during  convalescence,  the  specific  gravity  of  the  urine  is  low,  varying 
between  1.005  and  1.010.  In  many  cases  of  mild  infection  there  is  no  variation 
from  normal  in  the  specific  gravity. 

Color. — As  in  all  febrile  diseases  the  color  of  the  urine  is  increased  during 
the  attack,  being  usually  reddish  and  smoky  in  appearance.  It  generally 
deposits  a  considerable  sediment  of  urates  or  phosphates  upon  standing.  The 
color  of  the  urine  in  the  polyuria  of  convalescents  is  usually  a  pale  lemon- 
yellow. 

Reaction. — The  urine,  both  during  the  attack  and  in  convalescence  is 
acid  in  reaction,  the  acidity  being  greatly  increased  during  the  paroxysms  when 
the  urine  is  diminished  in  amount.  The  acidity  is  normal  when  the  urine  is 
excreted  in  normal  quantity. 

Total  Solids. — The  total  solids  are  increased,  especially  during  a 
malarial  attack. 

Urea. — The  amount  of  nitrogen  excreted  in  the  24  hours  is  increased  above 
normal,  this  increase  being  greatest  during  the  fever.  Sometimes  the  increase 
is  most  marked  before  the  fever,  while  after  the  paroxysm,  in  the  afebrile 
period,  the  amount  of  urea  eliminated  is  lowest,  but  is  not  below  normal.  In 
rare  instances  the  greatest  amount  of  urea  is  excreted  during  the  afebrile  period. 
The  increase  in  nitrogen  and  urea  eliminated  during  malarial  attacks  is 
undoubtedly  due  to  increase  of  tissue  waste  brought  about  by  the  action  of  the 
infection  upon  the  organism. 

The  urine  in  cases  of  malarial  polyuria  following  the  paroxysms  generally 
shows  a  decreased  amount  of  urea. 

Uric  Acid. — According  to  Rem-Picci,  no  special  law  controls  the  excretion 
of  uric  acid  during  attacks  of  malaria,  but  an  increase  during  the  fever  is 
rarely  observed  in  aestivo-autumnal  infections,  in  my  experience. 

Phosphates. — This  subject  has  been  studied  by  Rem-Picci,  Bernasconi, 
Rosenstein,  Gee,  and  Freund,  and  all  agree  in  stating  that  at  the  beginning  of 
the  paroxysms  there  is  a  marked  decrease  in  the  phosphates  in  the  urine,  followed, 
during  apyrexia,  by  a  marked  increase  in  the  excretion  of  phosphoric  acid,  thus 
proving  that  during  the  fever  there  is  a  retention  of  phosphates  in  the  body. 
The  amount  of  phosphates  excreted  during  the  24  hours  by  malarial  patients 
is  greater  than  normal.  The  phosphates  are  generally  increased  in  the  urine 
of  patients  suffering  from  the  polyuria  of  convalescence. 


142  THE    PATHOLOGY    OF    THE    MALARIAL   FEVERS. 

Chlorides. — The  chlorides  are  markedly  increased  during  the  fever, 
but  decrease  in  the  afebrile  period,  the  decrease  beginning  during  the  decline 
in  the  temperature.  In  convalescence  we  rarely  observe  an  increase  in  the 
chlorides. 

Sodium  and  Potassium. — The  amount  of  sodium  and  potassium  elimi- 
nated, as  well  as  the  period  of  elimination,  varies  considerably  in  different 
patients.  Rem-Picci  found  that  about  one  half  of  his  cases  showed  diminished 
sodium  and  potassium  during  pyrexia,  while  the  other  half  showed  a  diminution 
during  apyrexia.  More  sodium  was  eliminated  during  pyrexia  in  one  half, 
while  in  the  other  half  more  sodium  was  eliminated  during  apyrexia.  The 
increased  excretion  of  sodium  may  be  peculiar  to  malaria,  but  the  lack  of 
careful  observations  upon  the  urine  of  other  fevers  due  to  protozoa  leaves 
this  matter  still  in  doubt. 

Iron. — Colasanti  and  Iacoangelini  have  demonstrated  that  more  iron  is 
present  in  the  urine  of  malarial  patients  than  that  of  other  fevers,  and  that 
the  quantity  of  iron  is  greater  after  than  during  the  paroxysm.  The  increase 
in  iron  is  greatest  in  the  most  severe  infections. 

Albumin. — Albuminuria  occurs  with  varying  frequency  in  malarial 
patients  depending  upon  the  type  of  infection  and  upon  the  locality.  In  the 
tropics  albuminuria  is  much  more  common  in  malaria  than  in  the  temperate 
zones,  and  even  in  the  tropics  it  is  more  common  in  certain  severely  infected 
regions.  Albumin  appears  in  the  urine  of  a  certain  proportion  of  cases  of  the 
more  severe  tertian  and  quartan  infections,  and  in  the  majority  of  cases  of 
aestivo-autumnal  fevers.  In  the  latter  infections  hyaline,  epithelial,  and 
granular  casts  are  not  infrequently  observed,  and  it  can  be  stated  as  a  rule  that 
all  fatal  cases  of  malaria  show  albuminous  urine  before  death.  This  subject 
will  be  further  discussed  in  the  chapter  dealing  with  the  complications  of 
malaria. 

Peptone  is  found  very  rarely  in  the  urine  after  the  decline  of  the  tempera- 
ture as  reported  by  Botazzi  and  Pensuti. 

Nucleo-albumin  has  been  found  in  the  urine  of  malarial  patients  by 
Mannaberg,  urobilin  by  Kieweit  de  Jonge. 

Indican. — In  severe  aestivo-autumnal  infections,  especially  those  accom- 
panied by  severe  irritation  of  the  gastrointestinal  canal,  the  urine  shows  a 
a  marked  increase  in  the  amount  of  indican  excreted. 

The  Diazo-reaction. — The  diazo-reaction  occurs  not  so  very  infrequently 
in  cases  of  malaria,  especially  in  long-continued  aestivo-autumnal  infections. 
Thayer  and  Hewetson,  Mannaberg,  Zieman,  and  the  writer  have  all  observed 
this  reaction  in  the  urine  of  malarial  patients,  and  it  is  generally  acknowledged 
that  this  test  is  untrustworthy  in  the  diagnosis  between  malaria  and  typhoid. 
Horcicka  found  this  test  positive  in  7  per  cent,  of  the  tertian  cases,  in  12  per 
cent,  of  quartan  cases,  and  in  33  per  cent,  of  the  aestivo-autumnal  infections 
observed  by  him. 

Toxicity  of  the  Urine. — Several  observers  have  endeavored  to  ascertain 


THE    PATHOLOGY    OF    THE    MALARIAL    FEVERS.  I43 

whether  the  toxicity  of  the  urine  is  increased  in  malarial  infections,  much  good 
work  in  this  line  having  been  accomplished  by  Brousse,  Roque  and  Lemoine, 
and  Botazzi  and  Pensuti. 

Brousse's  conclusions  from  his  work  are  as  follows: 

"1.  The  urotoxic  coefficient  calculated  by  Bouchard's  formula,  the  mean 
coefficient  being  0.464,  rises  during  the  paroxysm,  and  the  physiological  effects 
observed  are  those  which  usually  follow  the  injection  of  urine-dyspnoea,  myosis, 
fall  of  temperature,  exophthalmos,  and,  furthermore,  convulsions. 

"2.  This  toxicity  is  diminished  during  the  period  of  convalescence  in  inter- 
mittent fever  very  much  below  that  of  the  urine  during  the  paroxysm,  and, 
moreover,  below  that  of  normal  urine." 

On  the  other  hand,  Botazzi  and  Pensuti,  following  the  method  of  Brousse 
in  injecting  malarial  urine  into  animals,  do  not  agree  with  the  latter  observer, 
but  conclude  that  the  experiments  do  not  prove  the  existence  of  a  specific 
toxin  in  malarial  urine.  Their  conclusions,  which  are  deserving  of  the  greatest 
consideration,  are  as  follows: 

"  1.  That  in  the  malarial  fevers  the  febrile  urine  is  less  toxic  than  that 
passed  during  the  apyretic  stage. 

"2.  That  the  urine  emitted  during  the  period  of  apyrexia  is  more  toxic  than 
normal  urine. 

"3.  That  the  toxicity  of  the  urine  of  malarial  patients  augments  constantly 
with  the  succession  of  febrile  attacks,  though  in  some  cases  this  augmentation 
appears  in  the  form  of  unexpected  and  irregular  exacerbations. 

"4.  That,  as  there  is  nothing  specific  in  the  course  of  the  intoxications 
produced  in  rabbits  with  malarial  urine,  there  is  no  need  to  suppose  the  presence 
of  specific  toxins  or  substances  of  the  nature  of  leucomaines,  for  the  salts  of 
potassium,  phosphoric  acid,  the  urinary  pigments,  the  peptones — all  of  which 
substances  are  eliminated  in  increased  quantities — are  a  sufficient  explanation. 

"  5.  That  the  injection  of  febrile  urine  is  followed  by  a  slower  intoxication, 
characterized  by  sopor,  by  increased  diuresis,  by  diarrhoea,  and  mydriasis,  while 
the  apyretic  urine  produces  a  more  acute  effect,  sometimes  fulminating,  char- 
acterized by  clonic  and  tonic  spasms,  myosis,  "exorbitisme,"  spastic  expiration. 

"  6.  That  to  explain  this  different  picture  one  may  suppose  that  with  febrile 
urine  the  polyuria  and  diarrhoea  are  due  chiefly  to  the  increased  richness  in  urea, 
while  the  peptones  may  contribute  to  the  production  of  sopor.  In  the  afebrile 
urines  the  salts  of  potassium,  the  phosphoric  acid,  the  urinary  pigments,  and 
especially  the  urobilin,  manifesting  themselves  as  substances  essentially  con- 
vulsive, determine  an  hypertoxicity. 

"7.  Finally,  besides  the  haemocytolysis,  the  destruction  of  the  cellular 
elements  of  the  tissues,  and  the  formation  and  elimination  of  toxic  substances, 
there  must  exist  intermediate  factors  which  account  for  the  absence  of  increased 
toxicity  after  the  first  febrile  paroxysms,  and  the  irregular  elevation  and  dimi- 
nution in  the  urotoxic  coefficient  in  some  other  cases." 

The  work  of  Botazzi  and  Pensuti  would  appear  to  show  that  while  the 
urine  in  malarial  cases  has  an  increased  toxicity  at  certain  times,  this  toxicity 
is  not  due  to  a  specific  toxin,  but  to  the  products  of  tissue  waste  and  haemoly- 
sis. Up  to  the  present  time  no  one  has  succeeded  in  demonstrating  a  specific 
malarial  toxin  in  the  urine  of  patients  suffering  from  the  disease. 


144  THE    PATHOLOGY    OF    THE    MALARIAL    FEVERS. 

Etiology  of  the  Fever. — In  the  regularly  intermittent  malarial  fevers, 
it  is  well  known  that  the  onset  of  the  fever  is  coincident  with  the  sporulation  of 
the  plasmodia.  The  same  is  true  in  the  more  irregular  aestivo-autumnal 
infections,  although  the  time  of  sporulation  of  the  plasmodia  is  not  so  easily 
recognized,  as  segmenting  forms  do  not  usually  occur  in  the  peripheral  blood. 
In  these  cases,  however,  blood  from  the  spleen,  obtained  by  puncture, 
will  also  show  a  preponderance  of  segmenting  forms  at  the  onset  of  the 
fever. 

To  what  is  the  fever  due  ?  Many  and  various  have  been  the  theories  held 
by  scientists  regarding  this  question.  Laveran  believed  that  the  febrile  attack 
was  due  to  nerve  irritation;  Richard,  that  it  is  the  index  of  the  reaction  of  the 
human  organism  to  the  malarial  plasmodia;  Golgi,  that  the  febrile  paroxysm 
is  due  to  the  invasion  of  the  red  blood-corpuscles  by  the  young  plasmodia, 
while  Antolisei  concluded  that  the  invasion  of  the  red  cells  by  the  plasmodia 
had  little  to  do  with  the  rise  of  temperature,  which  he  believed  to  be  due  to 
the  setting  free  in  the  blood-plasma  of  the  newly-born  plasmodia  at  the  time 
of  segmentation. 

To  Baccelli,  however,  we  owe  the  most  reasonable  theory  of  the  rise  of 
temperature  in  malaria,  and  the  one  which  is  to-day  accepted  by  most  authorities. 
He  suggested  that  during  sporulation,  and  the  consequent  liberation  of  the 
young  plasmodia  in  the  blood  plasma,  certain  toxic  products,  evolved  during 
the  growth  of  the  plasmodia,  were  also  liberated,  and  that  these  produced  the 
rise  in  temperature  and  the  characteristic  symptoms  of  a  malarial  paroxysm. 
The  toxic  products  he  considered  to  be  chemical  poisons  of  unknown  nature, 
the  amount  liberated  depending  upon  the  number  of  plasmodia  reaching  the 
stage  of  sporulation.  This  theory  has  been  accepted  by  Marchiafava,  Bignami, 
Golgi,  Thayer,  Zieman,  and  many  other  students  of  malaria.  I  believe  that 
this  theory  explains  most  rationally  the  rise  in  temperature  in  the  malarial  fevers, 
by  a  probable  direct  action  of  the  toxin  upon  the  heat  centers  and  upon  the 
vasomotor  system,  and  reasoning  from  analogy,  it  is  impossible  to  believe 
otherwise  than  that  the  fever  of  malaria  is  due  to  the  liberation  of  toxic  products 
in  the  blood  during  the  sporulation  of  the  plasmodia. 

While  we  must  admit  that  as  yet  we  have  no  positive  proof  of  the  existence 
of  a  specific  malarial  toxin  or  toxins,  yet  certain  facts  have  been  ascertained 
which  go  far  toward  establishing  this  theory  upon  experimental  evidence.  That 
toxic  products  are  eliminated  in  the  urine  in  malaria  I  have  already  shown, 
although  no  specific  toxin  has  been  found  in  this  fluid.  The  same  is  true  of 
the  perspiration  at  the  time  of  the  paroxysm,  as  shown  hy  Queirolo,  who 
found  that  such  perspiration  was  very  toxic  to  guinea-pigs,  while  the  perspira- 
tion of  normal  individuals  was  not.  The  occurrence  in  the  spleen,  liver, 
brain,  and  other  viscera  of  areas  of  focal  necrosis,  identical  with  those  described 
by  numerous  observers,  such  as  Welch,  Reed,  and  Flexner,  as  occurring  in 
other  acute  infections,  like  typhoid  and  diphtheria,  and  as  due  to  toxic 
substances  circulating  in  the  blood,  is  almost  positive  proof   that  malaria  is 


THE    PATHOLOGY    OF    THE    MALARIAL    FEVERS.  I.45 

a  toxaemia,  for  Flexner  has  proven  that  such  focal  areas  of  necrosis  are  charac- 
teristic of  a  general  toxaemia. 

The  recent  experiments  of  Rosenau,  Francis,  Parker,  and  Beyer  with 
filtered  blood  from  malarial  cases,  would  appear  to  indicate  that  the  blood 
serum  contains  a  toxin  capable  of  causing  the  symptoms  of  malaria  when 
injected  into  a  healthy  individual.  They  have  demonstrated  this  toxin  in  the 
blood  during  the  chill  in  tertian  infection,  but  were  unable  to  demonstrate  it 
in  the  blood  in  a  case  of  aestivo-autumnal  infection  during  the  decline  of  the 
paroxysm.  They  say:  "While  this  poison  reproduced  the  symptoms  of  the 
disease,  still  the  data  are  too  limited  to  consider  it  the  malarial  toxin."  The 
researches  of  Celli,  Mannaberg,  Gualdi,  and  others  regarding  a  malarial  toxin 
in  the  blood  resulted  negatively,  but  there  is  some  reason  to  believe  that  those 
of  Rosenau  and  his  confreres,  conducted  under  modern  precautions,  have  been 
successful  in  demonstrating  the  malarial  toxin.  However  that  may  be,  the 
occurrence  of  areas  of  focal  necrosis,  the  growth  of  connective  tissue,  which 
follows  malarial  infection,  the  clinical  symptoms  of  these  fevers,  the  degenerative 
changes  occurring  in  the  blood  and  in  the  tissue  cells,  all  point  to  a  specific 
toxin  as  the  etiological  factor. 

In  the  light  of  our  present  knowledge,  we  are  forced  to  conclude  that 
the  rise  of  temperature  in  all  malarial  fevers  is  due  to  a  toxic  substance  or  substances 
produced  by  the  Plasmodia  during  their  development,  and  liberated  at  the  time  of 
sporulation  of  these  organisms.  While  it  is  probable  that  toxic  materials  are 
formed  during  the  degeneration  and  breaking  up  of  the  red  corpuscles  in 
malaria,  I  believe  that  such  materials  have  but  little  to  do  with  the  production 
of  the  fever  and  the  characteristic  symptoms  of  the  disease. 

The  periodicity  of  the  rise  in  temperature  is  easily  explained  by  the  intervals 
of  time  elapsing  between  the  sporulation  of  the  plasmodia,  and  in  the  case 
of  continued  fevers,  by  the  fact  that  multiple  groups  of  plasmodia  are  present 
which  sporulate  at  short  intervals,  thus  causing  an  almost  constant  discharge 
of  toxic  material  into  the  circulation.  In  this  way  all  variations  in  the  tempera- 
ture curve  observed  in  malaria  may  be  explained,  the  sporulation  of  the 
plasmodia  initiating  the  temperature  and  the  clinical  symptoms. 

If  sporulation  be  delayed  we  have  an  anomalous  temperature  curve,  while 
if  a  double  or  triple  infection  with  various  species  of  plasmodia  occur  we 
have  an  irregular  or  almost  continuous  temperature  curve.  Infection  with 
two  groups  of  tertian  plasmodia  produces  a  quotidian  curve,  as  does  infection 
with  three  groups  of  quartan  organisms,  provided  both  varieties  sporulate  at 
intervals  of  twenty-four  hours.  A  quotidian  curve  is  also  produced  by  the 
quotidian  aestivo-autumnal  plasmodium  while  a  double  infection  with  this 
organism  may  produce  an  almost  continuous  temperature.  In  those  instances 
in  which  two  groups  of  quartan  parasites  sporulate  at  intervals  of  24  hours, 
a  temperature  curve  is  produced  characterized  by  a  rise  of  temperature  upon 
two  days,  with  one  day  of  normal  temperature  intervening.  The  temperature 
and  the  severity  of  the  clinical  symptoms  vary  according  to  the  species  of 


146  THE    PATHOLOGY    OF    THE    MALARIAL   FEVERS. 

Plasmodia  infecting  the  individual  and  the  number  of  plasmodia  present. 
Thus  the  plasmodia  causing  the  aestivo-autumnal  fevers  evidently  produce 
a  toxin  which  is  more  powerful  than  that  of  the  plasmodia  of  tertian  and 
quartan  infections,  for  in  the  former  class  of  infections  we  meet  with  the  vast 
majority  of  pernicious  symptoms,  and  this  though  the  plasmodia  may  not  be  as 
numerous  as  in  the  milder  infections.  In  general,  however,  the  symptoms 
increase  in  severity  with  the  number  of  plasmodia  present,  even  in  the  aestivo- 
autumnal  infections. 

In  rare  instances  fatal  pernicious  infections  are  observed  in  which  there  is 
little,  if  any  rise  of  temperature.  I  have  observed  a  fatal  case  of  aestivo- 
autumnal  infection  in  which  throughout  the  disease  the  temperature  was 
normal  or  subnormal,  yet  in  which  the  blood  from  the  spleen  showed  immense 
numbers  of  sporulating  aestivo-autumnal  plasmodia.  How  can  such  an 
absence  of  temperature  be  explained  ?  At  the  present  time  we  cannot  explain 
these  cases,  except  to  say  that  in  malaria,  as  in  other  diseases,  many  exceptions 
are  noted  to  the  general  rule,  and  unexplainable  idiosyncrasies  occur. 

After  a  malarial  infection  has  persisted  for  a  considerable  length  of  time,  it 
is  commonly  observed  that  even  though  the  plasmodia  may  be  demonstrated 
in  the  blood  and  undergo  sporulation  as  usual,  the  fever  becomes  modified  or 
disappears.  While  we  are  unable  to  state  definitely  the  reason  for  the  disap- 
pearance of  the  fever  in  these  infections,  it  is  probable  that  the  continued  action 
of  the  toxin  or  toxins  upon  the  organism  has  resulted  in  its  acquiring  a  relative 
immunity  to  the  fever-producing  toxin,  or  has  stimulated  the  production  of 
antitoxic  substances. 

The  subject  of  spontaneous  recovery  is  a  most  interesting  one  and  one  that 
will  well  repay  careful  investigation,  for  in  its  explanation  lies  the  secret  of  im- 
munity to  these  fevers.  If  we  understood  the  etiology  of  spontaneous  recovery 
we  would  undoubtedly  be  able  to  devise  some  method  of  producing  immunity, 
and  eventually  of  ridding  the  world  of  one  of  its  greatest  scourges  in  the  form  of 
disease. 

Literature  upon  the  General  Pathology  of  the  Malarial  Fevers. 

1847.      Meckel.      Ueber  schwarzes  Pigment  in  der  Milz  und  dem   Blut  einer 

Geisteskranken.      Zeitschr.  f.  Psychiatrie,  p.  193. 
1849.      Virchow.      Zur     pathologischen     Physiologie     des     Blutes.      Virchow's 

Archiv,  ii,  p.  587. 

1874.  Arnstein.      On    Malarial   Pigment    and  its    Origin.      Virchow's  Archiv, 
Bd.  lxi,  p.  494. 

1875.  Kelsch.      Contributions  a  l'anatomie  pathologique  des  maladies  palus- 
tres  endemiques.      Arch,  de  Physiologie,  p.  690. 

1876.  Idem.      Nouvelle  contribution  a   l'anatomie   pathologique   des   maladies 
palustres  endemiques.      Arch,  de  Physiologie.  ii  serie,  iii,  p.  490. 

1889.      Rossoni.      Lavori  dei  congressi  della  societa  italiana  di  medicina  interna, 

ii  congresso,  Roma,  Oct.,  p.  121. 
1 89 1.      Dionisi.      Lavori   del   III   congresso   della   societa   italiano   di   medicina 

interna,  Milan,  Oct.,  p.  169.      Also  Lo  Sperimentale,  iii  and  iv,  p.  284. 


THE    PATHOLOGY    OF    THE    MALARIAL   FEVERS.  147 

1894.      Colosanti  and  I acoangelini.      Atti  di  XI  cong.  de  medicina  interna. 

Roma,  iii,  p.  42. 
1892.      Baccelli.     Ueber    das     Wesen   der    Malariainfection.      Deutsch.    med. 

Woch.,  Aug.  11,  No.  32,  p.  721. 
1894.     Dock.     Pernicious  Malarial  Fever.     Am.  Jour.  Med.  Sciences,  vol.    cvii, 

No.  4,  p.  379. 
1894.      Golgi.      Ueber  die  romischen  Sommer-Herbst-Malariafieber.      Deutsch. 

Med.  Woch.,  Mar.  29,  No.  13. 

1894.  Botazzi    and    Pensuti.      Sulla    tossicita    dell'    orina  dei  malarici.      Lo 
Sperimentale.      Firenze,  xlviii,  p.  232,  254. 

1895.  Billings.     The  Leucocytes  in  Malarial  Fever.     J.  Hopkins  Hosp.  Bull., 
No.  43,  p.  105. 

1895.  Rem-Picci.      La  secrezione  urinaria  nella  infezione  malarica.   Bull.  dell. 
Regia  Accad.,  medica  di  Roma. 

1896.  Rem-Picci.      Nuovo  contributo  alio  stidio  della  eliminazione  dei  fosfati. 
Ibid. 

1897.  Plehn,  A.     Ueber  Blutbefund  und  Therapie  tropischer  Malaria- Erkrank- 
ungen.      Sonderabdruck  a.d.  Wiener  klin.  Rundschau,  No.  28. 

1898.  Bignami.     Die   Tropenfieber   und   die   Sommer   und   Herbstfieber,    etc. 
Centralbl.  f    Bakt.,  Bd.  xxiv,  Nos.  18-19,  p.  650. 

1898.  Zieman.      Ueber  malaria  und  andere  Blutparasiten.      Jena. 

1899.  Plehn,  A.      Die  Tropenanaemie,  etc.      Deutsch.  med.  Woch.,  Nos.  28-30, 
p.  465-482-500. 

1899.      Glogner.      Ueber  die  im  Malayischen  Archipel  verkommenden  Malaria- 
erreger,  etc.,  Virchow's  Archiv,   Bd,  clviii,  p.  444. 

1901.  Plehn,  A.      Weiteres  iiber  Malaria,  Immunitat  und  Latency.      Jena. 

1902.  Billet.      De  la  fievre  quarte.      Bull.  Med.  de  l'Algerie. 

1902.  Brown,  P.  K.      Acute     Lymphemia    with     Aestivo-autumnal     Malaria. 
Boston  Med    and  Surgical  Jour.,  iii,  p.  20. 

1903.  Rogers.      Malarial  Remittent  Fever.      Jour.   Tropical.  Med.,  Sept.  1,  p. 
272. 

1904.  Kieweit  de  Jonge.      Het  urobilinegehalte  der  urin  biz  malaria.      Mede- 
derlingen  wit  het  Generskundig  Laboratorium. 

1904.  Zeri,    A.      La  infezione  malarica  perniciosa.      II  Policlinico,  vol.  ii,  No.  4. 

1905.  Horcicka.      Ueber  die   Diazoreaktion  bei  Malaria  und  Typhus  abdom- 
inalis.      Arch.  f.  Schiffs-  u.  Tropen-Hyg.,  p.   533. 

1907.     Stephens  and  Christophers.     Practical  Study  of  Malaria  and  Blood 
Parasites.      London,  1908. 
Consult  also  the  monographs  upon   malaria   which   have  been   mentioned 
in  preceding  chapters. 


CHAPTER  II. 
The  Special  Pathology  of  Acute  Malarial  Infections. 

The  pathological  lesions  occurring  in  the  viscera  in  acute  malarial  infections 
are  similar  in  character  for  all  species  of  plasmodia,  although  more  severe 
lesions  are  usually  found  in  aestivo-autumnal  infections.  The  visceral  path- 
ology of  malaria  has  been  thoroughly  studied  by  numerous  observers,  among 
whom  may  be  mentioned  Bignami,  Laveran,  Guarnieri,  Councilman,  Abbott, 
.Dock,  Bastianelli,  Thayer,  Barker,  Monti,  and  Ewing.  In  recent  years  our 
knowledge  of  the  changes  occurring  as  the  result  of  malaria  in  the  viscera  has 
been  greatly  added  to  by  such  studies,  and  we  have  come  to  understand  better 
the  extensive  pathological  lesions  which  often  follow  these  infections.  I  cannot 
better  introduce  this  portion  of  our  subject  than  by  quoting  Marchiafava  and 
Bignami's  admirable  remarks  concerning  the  pathology  of  malaria.     They  say: 

"The  malarial  infection  develops  in  the  blood;  here  only,  and  chiefly  within 
the  red  corpuscles,  can  the  parasite  live.  From  this  it  follows  that  the  parasite 
invades  the  red  corpuscles  and  nourishes  itself  at  their  expense,  transforming 
the  coloring  matter  of  the  corpuscles  into  black  pigment  (which,  after  the 
multiplication  or  the  destruction  vof  the  parasite,  is  incorporated  into  the  white 
cells)  or  otherwise  injuring  the  red  corpuscles.  In  consequence  of  this  infection 
of  the  blood,  we  find,  in  addition  to  the  destruction  of  the  cells,  a  production  of 
the  detritus  of  the  red  corpuscles  and  of  the  parasites,  the  presence  of  pigmented 
white  cells,  and  the  penetration  of  erythrocytes  containing  parasites,  and  of 
leucocytes  containing  pigment,  into  the  capillaries  of  all  the  organs.  It  can  be 
understood  from  this  primary  localization  of  the  infection  how  the  principal 
changes  must  be  found  in  the  hematopoietic  organs  in  addition  to  the  blood, 
and  how  alterations  are  to  be  encountered  in  all  the  organs  and  tissues." 

This  brief  summary  furnishes  the  key  to  the  special  pathology  of  malaria, 
and  it  should  be  remembered  that  any  of  the  species  of  malarial  plasmodia  may 
cause  pernicious  symptoms  leading  to  the  death  of  the  patient,  and  that  the 
pathological  lesions  are  practically  similar  for  all  species  of  plasmodia. 

Appearance  of  the  Cadaver. — -The  skin  of  a  patient  dying  of  malaria  has 
a  peculiar  dusky-brown,  yellowish,  or  grayish  hue,  more  pronounced  the  longer 
the  infection  has  lasted,  and  most  pronounced  in  patients  suffering  from 
malarial  cachexia.  The  wasting  of  the  tissues  depends  upon  the  duration  of 
the  disease.  Rigor  mortis  appears  early,  and  is  only  moderate  in  extent,  but 
postmortem  discoloration  is  often  intense  and  appears  soon  after  death.  Not 
infrequently  jaundice  is  present  and  the  body  resembles  that  of  a  yellow-fever 
cadaver  externally. 

148 


THE    PATHOLOGY    OF    THE    MALARIAL    FEVERS.  149 

The  Brain. — As  most  patients  dying  of  pernicious  malarial  infection  suffer 
from  cerebral  symptoms,  the  brain  presents  marked  pathological  lesions.  In 
no  organ  are  the  pathological  changes  more  exquisitely  illustrated  than  in  the 
brain,  especially  in  those  patients  who  have  died  of  cerebral  forms  of  the  in- 
fection.    In  rare  cases  the  brain  will  appear  almost  normal. 

Macroscopic. — Externally  the  blood-vessels  are  generally  congested,  and 
the  entire  organ  appears  hyperaemic.  Small  capillary  hemorrhages  are  often 
observed  and  oedema  is  generally  present.  In  those  cases  in  which  no  cerebral 
symptoms  have  been  present  during  life  there  is  but  little  evidence  of  hyper- 
aemia.  Externally  the  brain  does  not  appear  pigmented  save  in  very  rare 
instances. 

Upon  section  the  cut  surface  is  generally  hyperaemic,  and  small  hemor- 
rhages, capillary  in  character,  may  be  present  in  the  gray  matter,  and  even  in 
the  white  matter.  The  lateral  ventricles  are  dilated  and  filled  with  fluid,  which 
may  be  blood-stained,  and  the  choroid  plexus  is  markedly  congested.  In  the 
majority  of  instances  the  cortex  is  of  a  brownish  or  chocolate  color,  due  to 
melanosis,  and  often  the  gray  matter  is  more  or  less  pigmented.  In  some  cases 
of  aestivo-autumnal  infection,  however,  the  brain  may  not  appear  pigmented. 
Small  hemorrhages  are  often  found  in  the  white  substance  and  also  in  the 
cerebellum.  In  not  a  few  cases  of  pernicious  malaria  the  brain  appears  anaemic 
and  no  pigmentation  can  be  detected.  The  congestion  and  hemorrhages  are 
due  to  blocking  and  rupture  of  the  capillaries  by  the  plasmodia,  free  pigment, 
cellular  detritus,  and  pigmented  leucocytes. 

Microscopic. — As  a  rule,  the  capillaries  of  the  brain  are  filled  with  blood 
corpuscles,  many  of  which  contain  plasmodia.  The  plasmodia  may  be  found 
to  be  in  various  stages  of  development,  or,  which  is  very  common,  all  of  them 
at  about  the  same  stage  of  development.  If  the  plasmodia  contain  much  pig- 
ment, as  in  tertian  and  quartan  infections,  and  in  some  aestivo-autumnal 
infections,  the  brain  appears  greatly  pigmented,  while  the  reverse  is  also  true. 
The  plasmodia  may  be  so  numerous  that  almost  every  red  corpuscle  is  invaded, 
or  they  may  be  very  few  in  number.  In  some,  instances  they  are  so  numerous 
as  to  occlude  the  lumen  of  the  capillaries,  thus  forming  thrombi.  The  small 
arteries  and  veins  are  less  rich  in  infected  corpuscles.  In  rare  cases  the  entire 
cycle  of  development  of  the  plasmodium  may  be  found  illustrated  in  one  capil- 
lary. Besides  infected  blood  corpuscles,  the  following  structures  may  be 
observed  in  the  capillaries: 

a.  Free  plasmodia. 

b.  Macrophages. 

c.  Free  pigment. 

d.  Pigmented  leucocytes. 

e.  Endothelial  cells. 

(a)  Free  Plasmodia. — In  some  cases  large  numbers  of  extracellular  or 
free  plasmodia,  always  pigmented,  are  observed  in  the  capillaries.  These 
plasmodia  are  always  round,  oval,  crescentic,  or  segmenting  bodies,  with  pig- 


150  THE    PATHOLOGY    OF    THE    MALARIAL    FEVERS. 

ment  in  the  form  of  a  solid,  minute  block,  situated  at  or  near  the  center.     These 
plasmodia  are  most  numerous  in  tertian  aestivo-autumnal  infections. 

(b)  Macrophages. — Immense  white  blood-corpuscles  containing  free 
pigment  and  plasmodia  are  generally  seen,  often  so  large  as  to  distend  and 
entirely  block  the  capillary  in  which  they  are  situated.  Most  of  these  cells  are 
of  endothelial  origin.  Smaller  phagocytic  leucocytes  are  often  present  and  may 
be  so  numerous  as  to  occlude  the  capillaries. 

(c)  Free  Pigment. — Many  of  the  capillaries  contain  much  free  pigment, 
which  sometimes  occurs  in  such  large  quantities  as  to  block  the  capillaries  and 
form  thrombi.  This  condition  is  generally  present  in  cases  which  have  pre- 
sented marked  comatose  symptoms. 

(d)  Pigmented  Leucocytes. — Most  of  the  leucocytes  present  in  the  brain 
capillaries  are  pigmented,  and  often  contain  red  corpuscles  containing  plasmo- 
dia.    The  leucocytes  are  usually  present  in  small  numbers. 

(e)  Endothelial  Cells. — The  endothelial  cells  lining  the  capillaries  are 
generally  swollen  and  are  undergoing  fatty  degeneration;  they  are  often  pig- 
mented, and,  by  reason  of  their  distention,  may  occlude  the  capillaries.  They 
often  occur  free  in  the  capillary  and  may  contain  plasmodia. 

Changes  in  the  Nerve-cells. — To  Marchiafava  and  Monti  we  are  in- 
debted for  valuable  contributions  upon  the  lesions  occurring  in  the  nerve-cells 
(ganglion  cells)  as  the  result  of  pernicious  malaria.  These  lesions  occur  in 
both  the  protoplasm  and  nucleus  of  the  nerve-cell.  In  the  protoplasm  the 
chromatic  bodies  of  Nissle  disappear,  and  the  protoplasm  appears  very  granular, 
or,  in  the  severest  cases,  the  protoplasm  appears  to  be  disintegrated  and  rarefied. 
The  nucleus  in  such  cells  may  appear  normal  or,  especially  in  the  pyramidal 
cells,  the  nuclear  membrane  and  nucleolus  disappear  as  well  as  the  chromatin, 
or  one  or  the  other  of  these  elements  may  persist.  Notable  changes  are  ob- 
served in  the  branches  of  the  cortical  cells,  consisting  of  attenuation  and  nodal 
formations  along  them,  or  they  may  present  a  beaded  appearance.  Sometimes 
very  large,  bleb-like  swellings  occur  along  their  dendrites,  connected  by  very 
slender  filaments  of  protoplasm.  In  rare  instances  nodes  are  observed  along 
the  axis  cylinders.  All  of  the  lesions  above  described  are  most  marked  in  fatal 
cases  of  comatose  aestivo-autumnal  malaria. 

Spinal  Cord. — Usually  the  spinal  cord  presents  no  lesions  of  importance  in 
malaria  but  in  rare  instances  lesions  similar  to  those  described  for  the  brain  are 
observed. 

The  Retina. — Guarnieri  has  studied  the  lesions  occurring  in  the  retina  in 
pernicious  malaria  and  finds  that  they  consist  in  congestion  and  hemorrhages, 
the  congested  vessels  containing  parasite-infected  red  corpuscles,  macrophages, 
pigmented  leucocytes,  and  free  pigment.  Many  of  the  capillaries  are  occluded, 
thus  leading  to  impairment  of  function. 

The  Lungs. — The  gross  pathology  of  the  lungs  in  cases  dying  of  pernicious 
malaria  is  not  characteristic,  there  being  usually,  according  to  the  stage  of 
the  disease  and  the  severity  of  the  infection,  hypostatic  congestion,  oedema, 


THE    PATHOLOGY    OF    THE    MALARIAL    FEVERS.  151 

capillary  hemorrhages,  or  areas  of  broncho-pneumonia  present.  Pigmenta- 
tion is  generally  present  but  cannot  be  distinguished  from  the  pigmentation  of 
anthracosis. 

Microscopic. — Sections  from  the  lungs  show  the  following  changes: 
The  alveolar  capillaries  are  generally  congested  and  often  contain  large  numbers 
of  pigmented  or  parasite-laden  leucocytes  which  are  often  much  degenerated. 
These  cells  are  most  numerous  in  the  smaller  arteries  and  capillaries.  The 
polynuclear  leucocytes  are  seldom  observed.  The  endothelium  of  the  capil- 
laries is  often  swollen  and  contains  small  particles  of  pigment,  but  this  condition 
is  very  much  less  marked  than  in  the  brain,  liver,  and  spleen. 

When  broncho-pneumonia  has  occurred,  the  exudation  into  the  alveoli  is 
mostly  composed  of  polynuclear  leucocytes,  and  the  alveolar  cells,  while  only  in 
rare  instances  are  pigmented  leucocytes  or  phagocytes  observed,  though  the 
alveolar  capillaries  are  often  crowded  with  them.  Neither  is  free  pigment 
common  in  this  exudation,  but  in  one  case  I  have  observed  parasite-infected  red 
cells  in  the  alveolar  exudation  in  a  case  in  which  the  symptoms  were  those  of  a 
severe  lobar  pneumonia.  Marchiafava  and  Bignami  claim  that  this  lack  of 
diapedesis  of  the  pigmented  leucocytes  and  macrophages  is  due  to  the  fact  that 
these  cells  are  degenerated  and  have  lost  the  power  of  amoeboid  motion  by 
which  they  are  normally  enabled  to  pass  through  the  capillary  walls.  In  cer- 
tain cases  areas  of  hemorrhage,  microscopic  in  character,  are  observed  in 
section  of  the  lung. 

When  pneumonia  complicates  the  pernicious  malarial  fevers  it  is,  without 
doubt,  due  to  the  diplococcus  of  pneumonia,  or  streptococci,  and  the  symptoms 
and  lesions  are  influenced  by  the  coexisting  malarial  infection. 

The  Heart. — There  is  but  little  that  is  characteristic  in  the  appearance  of 
the  heart  in  cases  of  pernicious  malaria.  In  very  severe  cases  the  organ  is 
somewhat  pigmented  and  the  heart  muscle  is  flabby  and  anaemic.  The 
chambers  of  the  heart,  especially  the  right  ventricle,  may  contain  clots,  in  which 
may  be  demonstrated  infected  red  corpuscles,  and  pigmented  leucocytes  and 
endothelial  cells. 

Microscopical. — The  endomysium  may  contain  many  mast  cells,  and 
rarely  fatty  degeneration  of  the  muscle  fibers  occurs.  The  capillaries  of  the 
muscular  wall  of  the  heart  may  contain  numerous  plasmodia,  both  free  and 
within  red  corpuscles,  as  well  as  pigmented  leucocytes.  Ewing  describes  a  case 
in  which  cardiac  failure  was  the  most  prominent  symptom  and  in  which  the 
heart  muscle  contained  a  greater  proportion  of  plasmodia  and  pigmented 
leucocytes  than  either  the  spleen  or  liver.  A  somewhat  similar  case  has  been 
reported  by  Benvenuti,  but  it  is  problematical  whether  malarial  infection  can  so 
weaken  the  heart  muscle  through  the  engorgement  of  the  capillaries  and  their 
occlusion  as  to  cause  the  death  of  the  patient. 

The  Stomach  and  Intestines. — Macroscopically,  the  only  change  usually 
observed  in  the  stomach  and  intestines  is  more  or  less  pigmentation,  the  mucous 
membrane  being  of  a  dull  slate  color  or  a  dark  brown  or  chocolate  color.     In 


1^2  THE    PATHOLOGY    OF    THE    MALARIAL    FEVERS. 

cases  dying  of  the  choleraic  form  of  pernicious  malaria,  the  lesions  are  more 
marked,  consisting  of  hyperaemia,  necrosis,  and  even  ulceration  of  the  mucous 
membrane.  In  such  cases  the  mucous  membrane  is  swollen,  inflamed,  and 
areas  of  capillary  hemorrhage  and  superficial  necrosis  are  observed.  The 
intestine  may  contain  blood-stained  mucus.  Peyer's  patches,  as  well  as  the 
solitary  glands,  are  often  greatly  swollen  in  severe  choleraic  malaria. 

Microscopic. —Sections  of  the  stomach  and  of  the  intestines  show  that  the 
capillaries  are  distended  with  blood,  and  in  the  intestines,  especially,  the 
capillaries  of  the  villi  are  crowded  with  parasite-infected  corpuscles,  free 
Plasmodia  and  pigment,  phagocytes,  and  endothelial  cells.  These  may  occlude 
the  capillaries,  forming  thrombi,  with  resulting  necrosis  and  ulceration  of  the 
mucous  membrane  in  places.  The  epithelium  lining  the  mucous  membrane  is 
often  necrotic,  and  there  may  be  present  a  very  general  superficial  necrosis  of 
this  membrane,  involving  only  the  epithelial  layer.  Beneath  the  areas  of 
necrosis  there  is  a  dense  infiltration  with  leucocytes,  and  bacteria  cf  various 
species  are  found  in  the  necrotic  tissue  and  invading  the  submucosa  beneath 
the  necrotic  areas. 

The  Adrenal  Glands. —Barker  has  carefully  described  the  lesions  of  acute 
malaria  occurring  in  the  adrenal  glands.  The  arteries  and  veins  contain  many 
Plasmodia,  bacteria,  pigmented  leucocytes,  plasmodia  within  red  corpuscles, 
and  a  few  macrophages.  The  vessels  are  distended,  and  there  occur  areas  of 
capillary  and  venous  dilatation.  Polynuclear  and  mononuclear  leucocytes  are 
present  containing  plasmodia,  the  polynuclear  cells  being  present  throughout  the 
gland,  the  mononuclear  being  found  between  the  vessel  walls  and  the  adrenal 
cells  of  the  zona  fasciculata.  The  endothelial  cells  of  the  organ  act  as  phago- 
cytes, as  in  the  liver  and  spleen,  and  a  few  of  the  adrenal  cells  may  contain 
pigment  and  infected  corpuscles.  Evidences  of  degeneration  are  observed  in 
the  adrenal  cells,  many  of  which  are  swollen,  fatty,  and  vacuolized,  and  show 
fragmented  nuclei.  The  changes  in  these  glands  are  very  suggestive  of  a 
toxaemia. 

The  Liver. — The  lesions  of  acute  malarial  infection  are  generally  well 
marked  in  this  organ  and  many  of  them  are  absolutely  characteristic. 

Macroscopic. — The  organ  is  generally  enlarged,  sometimes  markedly  so, 
but  usually  the  enlargement  is  slight  and  sometimes  not  appreciable.  The 
consistence  of  the  organ  is  reduced.  Pigmentation  is  always  present,  the 
color  varying  from  a  brownish  shade  to  black  upon  section.  The  capsule 
is  smooth  and  the  lobules  generally  indistinct.  The  gall  bladder  is  generally 
distended  with  almost  black  bile,  and  the  walls  of  this  organ  may  be  greatly 
pigmented.  Upon  section,  the  cut  surface  varies  in  color  from  a  very  dark 
brownish-red  or  a  slate  color  to  black,  and  is  bathed  in  blood,  as  the  organ  is 
usually  greatly  congested.  It  is  not  uncommon  to  find  the  cut  surface  mottled 
with  light  yellow  spots  due  to  fatty  degeneration. 

Microscopic. — The  lesions  characteristic  of  malarial  infection  are  found 
in  the  capillaries,  in  the  liver  cells,  and  in  the  connective  tissue  of  the  organ. 


THE    PATHOLOGY    OF    THE    MALARIAL   FEVERS.  1 53 

The  capillaries  contain  many  large  macrophagi,  containing  much  pigment, 
Plasmodia  and  sometimes,  red  corpuscles.  In  many  of  the  capillaries  the  lumen 
of  the  vessel  is  occluded  by  these  macrophagi,  or  by  free  pigment  and  cellular 
detritus.  The  number  of  parasite-infected  red  corpuscles  is  very  limited  in  this 
organ,  as  a  rule,  although  I  have  seen  sections  in  which  they  were  very  numerous. 
The  endothelial  cells  are  very  active  as  phagocytes  and  large  irregular  masses 
of  protoplasm,  filled  with  pigment  and  degenerated  plasmodia,  and  formed  by 
the  fusion  of  two  or  more  endothelial  cells,  are  not  infrequently  observed 
blocking  the  capillaries  of  the  liver. 

The  cells  of  Kupfer  form  a  considerable  proportion  of  the  phagocytic  cells, 
being  swollen  and  containing  pigment  and  fragmented  plasmodia. 

The  liver  cells  exhibit  various  forms  of  degeneration,  being  swollen, 
atrophied,  necrotic  or  vesiculated.  In  many  cases  the  liver  cells  contain  fine 
granules  of  yellow  pigment  (haemosiderin)  and  in  some  instances  the  proto- 
plasm is  entirely  replaced  by  this  pigment.  This  pigmentation  of  the  liver 
cells  is  not  characteristic  of  malaria,  and  is  generally  most  pronounced  toward 
the  center  of  the  liver  lobules.  A  peculiar  hyaline  degeneration  of  the  nuclei 
of  the  liver  cells  is  rarely  observed  in  pernicious  cases  of  malaria,  which  is 
characteristic  of  this  class  of  infections. 

The  central  veins  of  the  lobules  are  dilated  with  corpuscles  and  in  many 
places  small  haemorrhagic  areas  have  been  formed  by  the  rupture  of  capillaries 
and  smaller  blood-vessels,  and  the  surrounding  liver  tissue  becomes  infiltrated 
with  infected  red  corpuscles,  leucocytes,  phagocytes  and  free  pigment.  The 
congestion  of  the  capillaries  causes  pressure  atrophy  of  the  columns  of  liver 
cells  in  places,  and  entire  liver  lobules  may  thus  be  practically  composed  of 
dilated  capillaries,  the  liver  cells  having  completely  atrophied. 

Focal  Necrosis. — Areas  of  focal  necrosis,  such  as  have  been  described  by 
Reed  in  typhoid,  and  by  Welch  and  Flexner  in  diphtheria,  are  often  observed 
in  the  liver  in  severe  pernicious  malarial  infections.  These  areas  certainly 
indicate  that  a  specific  toxin  circulates  in  the  blood  in  malaria,  and  both  Barker 
and  Flexner  believe  that  they  are  due  to  a  general  toxaemia.  The  areas  of  focal 
necrosis  vary  in  size,  the  liver  cells  are  undergoing  hyaline  degeneration,  while 
polynuclear  and  mononuclear  cells  are  present  in  abundance,  and  capillary 
thrombi  are  seen,  oftentimes  multiple  in  character.  Following  the  necrosis 
there  is  a  proliferation  of  connective  tissue  in  the  vicinity,  starting  from  the 
portal  spaces,  with  the  formation  of  new  bile  ducts  and  changes  in  the  liver 
cells  similar  to  those  in  the  early  stages  of  cirrhosis. 

The  changes  occurring  in  the  connective  tissue  of  the  liver  consist  in  an 
infiltration  of  the  portal  spaces  by  round  cells  and  the  proliferation  of  connective 
tissue  following  focal  necrosis.  The  question  of  a  malarial  cirrhosis  is  one  of 
personal  susceptibility,  in  large  measure,  as  is  shown  by  the  rarity  of  this  condi- 
tion in  malarial  regions  and  among  those  who  have  suffered  from  repeated 
attacks  of  the  disease,  but  I  believe  that  such  a  form  of  cirrhosis  does  rarely 


154  THE    PATHOLOGY    OF    THE    MALARIAL    FEVERS. 

The  periphery  of  the  liver  lobules  and  the  portal  spaces  are  generally 
much  pigmented,  but  occasionally  the  pigment  is  scattered  in  irregular  masses 
throughout  the  lobules  being  contained  in  macrophages  within  the  capillaries, 
or  in  haemorrhagic  areas  within  some  portion  of  the  lobule.  In  some  cases  the 
spaces  between  the  capillary  wall  and  the  liver  cells  are  greatly  enlarged  and  are 
filled  with  phagocytic  Kupfer's  cells,  containing  free  pigment,  infected  red 
corpuscles,  free  plasmodia,  and  even  small  leucocytes. 

The  Spleen. — The  spleen  presents  the  most  characteristic  lesions  of 
malarial  infection  of  all  the  viscera,  and  a  smear  from  the  cut  surface  of  this 
organ  will  clinch  the  diagnosis  of  malaria  in  every  doubtful  case. 

Macroscopic. — The  spleen  is  always  enlarged,  sometimes  enormously  so. 
The  enlargement  generally  depends  upon  the  length  of  time  the  infection  has 
lasted,  the  largest  spleens  being  observed  in  cases  which  have  suffered  from 
repeated  and  severe  acute  attacks  of  the  disease.  As  a  rule,  the  organ  is  pig- 
mented externally,  varying  in  color  from  a  light  chocolate  to  black.  The  capsule 
is  tense  and  smooth,  and  the  consistence  greatly  diminished.  The  cut  surface 
is  of  a  chocolate,  slate,  or  jet-black  color,  and  in  many  cases  the  splenic  pulp 
is  so  soft  as  to  be  diffluent.  The  Malpighian  corpuscles  may  be  invisible  or 
visible  as  minute  white  dots  scattered  through  the  parenchyma.  In  cases 
dying  from  an  initial  pernicious  attack,  the  spleen  may  not  be  pigmented.  The 
enlargement  of  the  spleen  is  often  slight  in  aestivo-autumnal  infections. 

Microscopic. — The  venous  sinuses  of  the  spleen  are  congested  and 
dilated,  thus  hindering  the  circulation,  and  resulting  in  the  production  of 
irregular  haemorrhagic  areas  in  the  parenchyma.  The  sinuses  contain  multi- 
tudes of  plasmodia,  either  free  or  in  red  corpuscles,  as  well  as  enclosed  in  im- 
mense macrophages  and  smaller  mononuclear  or  polynuclear  cells.  The 
number  of  infected  red  cells  within  the  sinuses  is  often  enormous,  almost  every 
corpuscle  containing  one  or  more  plasmodia,  and  this  is  especially  true  in 
aestivo-autumnal  infections.  I  have,  however,  observed  cases  in  which  but 
few  red  corpuscles  were  demonstrable  in  the  spleen. 

The  cells  of  the  splenic  pulp  are  pushed  apart  by  the  multitudes  of  red 
corpuscles  which  contain  plasmodia  in  various  stages  of  development,  the  pig- 
mented forms  and  the  sporulating  bodies  being  most  frequently  observed. 
Free  plasmodia  are  less  common  but  by  no  means  rare.  In  aestivo-autumnal 
fever,  in  cases  which  have  lasted  for  several  days,  crescents  are  found,  but  I 
have  never  observed  them  in  large  numbers  and  they  are  often  absent  even 
when  they  may  be  demonstrated  in  the  peripheral  blood. 

Besides  the  parasite-infected  red  corpuscles,  the  sinuses  contain  an  im- 
mense number  of  phagocytic  cells,  consisting  of  small  cells,  resembling  lympho- 
cytes, which  are  few  in  number,  and  immense  macrophages,  which  are  much 
more  numerous  in  the  spleen  than  in  the  liver.  The  latter  cells  often  pre- 
sent evidence  of  degeneration,  as  shown  by  fatty  changes  and  necrosis  of  the 
protoplasm. 

The  smaller  vessels  of  the  spleen  are  congested  and  filled  with  infected  red 


THE    PATHOLOGY    OF    THE    MALARIAL    FEVERS.  155 

cells,  phagocytic  leucocytes  and  endothelial  cells,  and  free  pigment  and  plasmo- 
dia.  Free  pigment  is  present  throughout  the  pulp  sinuses,  lying  in  large  blocks 
or  clumps  or  in  the  form  of  minute  rods  and  granules.  Here,  as  in  the  liver, 
two  forms  of  pigment  occur:  the  dark  brown  or  nearly  black  malarial  pigment 
or  melanin,  and  the  golden-yellow  pigment  derived  from  the  degenerated  and 
broken-down  red  corpuscles,  haemosiderin. 

Areas  of  focal  necrosis,  exactly  similar  to  those  described  as  occurring  in  the 
liver  are  sometimes  observed  in  the  parenchyma  of  the  spleen,  and  pressure 
necrosis  of  minute  areas,  due  to  the  distended  or  ruptured  capillaries,  is  a  com- 
mon lesion. 

The  connective  tissue  of  the  spleen  is  not  increased  in  very  acute  infections, 
but  in  those  cases  which  die  of  an  acute  attack  following  repeated  attacks  of 
malaria,  the  connective  tissue  of  the  trabeculae  may  be  increased  in  amount. 
Pigmentation  of  the  fibrous  trabeculae  is  almost  always  observed,  but  the  Mal- 
pighian  corpuscles  are  not  pigmented,  although  a  considerable  amount  of  pig- 
ment generally  surrounds  these  bodies.  Thrombosis  is  a  common  lesion  in  the 
spleen.  In  rare  instances  there  is  but  little  evidence  in  the  spleen  of  malarial 
infection,  even  though  death  has  occurred  from  that  disease.  Bloombergh  and 
Coffin  report  a  case  in  which  no  plasmodia  could  be  demonstrated  in  sections  of 
the  spleen,  although  the  plasmodia  were  demonstrated  in  the  peripheral  blood, 
and  I  have  observed  at  least  two  fatal  cases  of  malaria  in  which  the  plasmodia 
were  so  few  in  smears  from  the  spleen  that  a  long  search  was  required  before 
they  could  be  demonstrated. 

The  Kidneys. — As  a  rule,  the  macroscopical  appearance  of  the  kidney  is 
not  at  all  characteristic  of  malaria.  The  organs  are  generally  slightly  enlarged, 
the  capsule  smooth,  the  consistence  decreased,  while  there  may  be  marked  con- 
gestion, and  in  rare  instances,  considerable  pigmentation.  The  cut  surface  is 
generally  congested,  and  the  cortex  may  appear  slightly  thickened.  The 
capsule  strips  readily.  The  appearances  presented  in  an  acute  parenchy- 
matous nephritis  are  by  no  means  rare,  accompanied  by  small  haemorrhages  in 
the  cortex  of  the  organ. 

Microscopical. — Aside  from  the  purely  malarial  lesions  present,  the 
microscopic  pathology  of  the  kidneys  in  pernicious  malaria  is  that  of  an  acute 
or  subacute  parenchymatous  nephritis,  but  the  lesions  peculiar  to  malaria  are 
much  less  marked  than  in  the  other  viscera,  especially  the  brain,  liver,  and  spleen. 

The  Malpighian  tufts  are  often  found  congested  and  the  seat  of  small 
capillary  haemorrhages.  There  is  but  little  pigmentation,  but  sometimes  the 
glomeruli  appear  greatly  pigmented,  the  pigment  being  situated  within  phagocytic 
cells  in  the  capillaries,  and  in  the  endothelial  and  epithelial  cells.  Plasmodia, 
either  free  or  within  red  corpuscles,  may  be  seen  occasionally  within  the  glomeru- 
lar capillaries,  but  they  are  generally  few  in  number.  The  epithelium  of 
Bowman's  capsule  shows  some  proliferation,  and  the  capsular  space  may  be 
filled  by  it  or  by  fibrinous  material,  in  which  may  be  imbedded  pigmented 
leucocytes  and  plasmodia. 


156  THE    PATHOLOGY    OF    THE    MALARIAL    FEVERS. 

The  epithelium  lining  the  convoluted  tubules  presents  cloudy  swelling, 
fatty  degeneration,  or  necrosis.  The  straight  tubules  often  contain  hyaline, 
epithelial,  or  granular  casts.  The  intertubular  capillaries  are  somewhat  con- 
gested and  in  them  free  pigment  in  small  amount  is  observed,  as  well  as  endo- 
globular  plasmodia,  pigmented  leucocytes,  and  macrophages.  In  some 
instances  capillary  haemorrhages  have  occurred  into  the  parenchyma  and 
areas  of  pressure  necrosis  may  be  present. 

In  very  rare  instances  the  organ  may  appear  greatly  pigmented  macroscop- 
ically,  the  cortex  appearing  dark  gray  in  color,  while  the  pyramidal  vessels  may 
be  distinctly  outlined  by  the  large  pigment  deposits  within  them. 

The  lesions  in  the  kidneys  which  result  from  malarial  infection  are  un- 
doubtedly due  to  a  toxic  poisoning,  as  the  plasmodia  are  present  in  too  small 
numbers  to  produce  the  grave  lesions  which  are  not  seldom  found  in  these  organs. 

The  Bone-marrow. — Macroscopically,  the  bone-marrow  varies  in  color 
according  to  the  length  of  time  the  infection  has  lasted.  In  the  long  bones,  in 
recent  cases,  the  normal  yellow  color  of  the  marrow  is  found;  while  if  the  in- 
fection has  lasted  for  some  time  the  color  varies  from  red  to  black.  Generally 
in  acute  cases  there  is  a  chocolate  color  observed.  There  may  be  an  extensive 
hyperplasia  of  the  marrow  in  severe  and  rapidly  fatal  cases. 

Microscopic. — In  sections  of  bone-marrow  the  lesions  observed  are  very 
similar  to  those  observed  in  the  spleen.  The  capillary  vessels  contain  numer- 
ous endoglobular  plasmodia  in  advanced  stages  of  development,  sporulating 
bodies,  and,  if  the  infection  has  persisted  long  enough,  crescents.  They  also 
contain  numerous  macrophages  inclosing  granules  and  clumps  of  pigment,  as 
well  as  red  blood-corpuscles  and  plasmodia.  External  to  the  capillaries,  in  the 
marrow  pulp,  plasmodia  are  found  in  various  stages  of  development,  and 
numerous  crescentic  plasmodia  or  gametes  may  be  present  in  aestivo-autumnal 
infections.  Here  are  also  found  many  large  macrophages,  some  of  which  are 
undergoing  degenerative  changes.  Nucleated  red  corpuscles  are  common  as 
well  as  pigmented  medullary  cells.  The  leucocytes  may  be  greatly  increased  in 
number. 

The  pathological  changes  in  the  other  viscera  are  of  little  importance  and 
do  not  merit  description. 

The  following  autopsy  record  of  a  case  dying  of  a  quotidian  aestivo-autum- 
nal infection  is  inserted  to  illustrate  the  lesions  most  commonly  found  in  the 
malarial  fevers. 

R.  G.  C. — Age  fifty-two  years.  White.  Clinical  diagnosis,  pernicious 
quotidian  aestivo-autumnal  fever. 

Body  that  of  a  man  apparently  fifty  years  of  age,  somewhat  emaciated. 
Skin  yellowish  in  color.  Rigor  mortis  slight.  Postmortem  discoloration 
marked  over  dependent  portion  of  the  body.  Finger-nails  not  congested. 
Pupils  regularly  dilated.  Marked  anaemia  of  the  mucous  membranes  and  of 
the  skin. 

Brain. — The  dura  mater  appears  normal.     The  amount  of  cerebrospinal 


THE    PATHOLOGY    OF    THE    MALARIAL    FEVERS.  1 57 

fluid  is  increased.  The  surface  of  the  cerebrum  is  pale,  and  upon  section  the 
medulla  appears  hyperaemic,  and  the  cortex  is  a  dark  slate  color.  The  lateral 
ventricles  are  filled  with  fluid.  The  choroid  plexus  is  not  congested.  The 
cerebellum,  upon  section  appears  normal. 

Thoracic  and  Abdominal  Cavities. — The  pleural  cavities  are  free 
from  fluid.  The  liver  reaches  about  one  centimeter  below  the  border  of  the 
last  rib.  The  omentum  contains  a  large  amount  of  fat,  and  reaches  the  level 
of  the  umbilicus.  The  appendix  is  about  three  centimeters  in  length,  and 
lies  in  the  right  iliac  fossa;  it  is  normal  in  appearance.  The  bladder  is  filled 
with  urine.     Abdominal  aorta  shows  no  sclerosis. 

Liver. — The  liver  measures  28  x  21  centimeters.  The  organ  is  purplish- 
black  in  color  externally  and  the  capsule  is  smooth.  The  gall-bladder  contains 
a  large  number  of  gall-stones  and  much  inspissated  bile.  Upon  section  the 
cut  surface  of  the  liver  is  slate  colored,  and  the  lobules  are  ill  defined.  The 
organ  is  greatly  congested.     Weight,  1,640  grams. 

Spleen. — The  spleen  measures  19  x  12  centimeters.  The  organ  is  almost 
black  in  color  externally  and  the  capsule  is  distended  and  smooth.  Upon 
section  the  cut  surface  is  black  in  color,  with  light  gray  areas  scattered  through 
it,  marking  the  location  of  the  Malpighian  corpuscles.  The  consistence  of 
the  organ  is  very  much  decreased,  it  being  almost  diffluent.  Weight,  440 
grams. 

Pancreas. — The  pancreas  measures  22  x  4.5  centimeters.  Upon  section 
the  cut  surface  appears  congested.     Weight,  115  grams. 

Kidneys. — Both  kidneys  appear  somewhat  congested.  The  capsule  is 
smooth  and  slightly  adherent.  Upon  section  the  cut  surface  is  congested,  but 
the  cortex  and  pyramids  are  distinct,  the  cortex  being  slightly  thickened. 
Weight  of  each  kidney,  125  grams. 

Lungs. — The  lungs  are  crepitant  throughout  and  appear  normal. 

Pericardial  Cavity. — The  pericardial  cavity  contains  about  3  ex.  of 
clear  straw-colored  fluid.     Both  layers  of  the  pericardium  appear  normal. 

Heart. — The  amount  of  extracardial  fat  is  increased.  The  blood-vessels 
are  congested.  Upon  section  of  the  heart  the  ventricles  are  found  to  contain 
small  clots.  The  muscular  walls  are  about  normal  in  thickness,  and  the 
valves  of  the  heart  are  normal  in  appearance. 

Microscopical  Examination. — The  Liver. — The  fibrous  tissue  in  the 
portal  spaces  is  slightly  increased  in  amount,  and  large  numbers  of  small  round 
cells  are  present  in  this  tissue.  All  the  blood-vessels  in  the  sections  are  increased 
in  thickness.  The  liver  cells  are  swollen,  smoky,  and  granular  in  appearance, 
and  in  many  of  them  the  nucleus  has  disappeared.  In  others  the  nucleus  is 
present,  exhibiting  necrotic  changes,  as  evidenced  by  loss  of  staining  power, 
and  the  absence  or  diminished  staining  of  the  chromatin  granules.  The 
protoplasm  of  the  liver  cells  contains  much  fine  yellow  pigment,  but  this  pigment 
is  not  found  within  the  nucleus  of  the  cells. 

The  intralobular  capillaries  contain  a  great  deal  of  black  pigment,  numer- 


158  THE    PATHOLOGY    OF    THE    MALARIAL    FEVERS. 

ous  macrophages,  and  smaller  mononuclear  leucocytes.  The  free  pigment 
in  the  capillaries  is  in  the  form  of  irregular  blocks,  and  the  yellow  pigment, 
so  common  in  the  protoplasm  of  the  liver  cells,  does  not  appear  within  the 
capillaries.  The  macrophages  which  crowd  the  capillaries  contain  within 
their  protoplasm  an  immense  amount  of  black  pigment,  evidently  derived 
from  broken-doAvn  plasmodia;  they  also  contain  infected  red  blood-corpuscles 
and  free  plasmodia  of  the  quotidian  aestivo-autumnal  variety.  The  number  of 
plasmodia  present  is  comparatively  small,  but  the  amount  of  pigment  is  immense, 
and  it  occurs  in  clumps  so  large  that  many  of  the  capillaries  are  occluded  by 
it.  This  condition  is  especially  noticeable  in  the  capillaries  near  the  portal 
spaces.  On  account  of  the  small  caliber  of  the  capillaries  the  macrophages 
are  often  compressed,  appearing  as  long,  slender,  pigment-bearing  cells.  The 
plasmodia  present  are  small,  round,  or  oval  bodies,  containing  a  few  small 
granules  or  grains  of  pigment,  generally  collected  at  the  center  of  the  organism. 
Most  of  these  are  presegmenting  plasmodia.  No  crescents  {gametes)  are 
present  in  the  liver.  The  stellate  cells  of  Kupfer  contain  black  pigment  and 
sometimes  small  plasmodia. 

In  numerous  situations  throughout  the  capillaries  of  the  liver  there  occur 
large,  bleb-like  plasmodia,  containing  pigment,  which  are  probably  degenerating 
parasites.  There  is  not  a  single  capillary  in  the  sections  that  does  not  contain 
pigment-bearing  cells  or  a  few  plasmodia. 

The  Spleen. — The  Malpighian  bodies  are  somewhat  fibrous,  and  at  their 
border  there  is  a  large  amount  of  yellowish-brown  pigment.  The  splenic  pulp 
contains  a  small  number  of  red  corpuscles  showing  small,  round,  or  oval  plas- 
modia within  them,  all  of  which  are  pigmented.  The  sinuses  contain  numerous 
infected  red  cells,  immense  numbers  cf  macrophages,  and  large  masses  of 
free  pigment  The  macrophages  contain  the  following:  (1)  large  irregular 
collections  of  brownish-black  pigment;  (2)  red  corpuscles  containing  pigmented 
aestivo-autumnal  plasmodia;  (3)  free  plasmodia,  most  of  them  pigmented 
and  showing  signs  of  segmentation;  (4)  fine  granules  of  a  yellowish  pigment 
which  is  distinct  from  the  large  amount  of  dark  brown  or  black  pigment  present. 
Some  of  the  macrophages  show  all  of  these  bodies  within  their  protoplasm, 
while  others,  and  they  are  in  the  majority,  show  only  one  or  two  free  plasmodia 
and  irregular  collections  of  pigment.  As  a  rule,  the  macrophages  are  about 
six  to  eight  times  as  large  as  a  normal  red  corpuscle,  but  many  are  present  which 
are  much  larger  and  entirely  block  the  capillaries. 

Besides  the  macrophages  there  are  many  mononuclear  leucocytes  and 
endothelial  cells,  which  are  free  from  plasmodia  or  pigment.  The  polynuclear 
leucocytes  are  comparatively  few  in  number.  Everywhere  throughout  the 
sections  there  are  very  large  masses  of  free  pigment  situated  in  the  splenic 
sinuses,  and  in  many  places  rupture  of  the  sinues  has  occurred  and  areas  of 
pressure  necrosis  have  formed. 

Throughout  the  sections  of  the  spleen  may  be  seen  crescentic  forms  of  the 
quotidian  aestivo-autumnal  plasmodium,  but  only  in  small  numbers.     In  the 


THE  PATHOLOGY  OF  THE  MALARIAL  FEVERS.  1 59 

spleen  there  are  also  bleb-like  degenerating  plasmodia,  like  those  in  the  liver. 
The  sporulating  forms  of  the  plasmodium  are  remarkably  few  in  number, 
but  many  of  the  macrophages  contain  sporulating  bodies. 

The  Kidneys. — Sections  of  the  kidneys  show  the  lesions  of  acute  paren- 
chymatous nephritis  and  some  lesions  characteristic  of  pernicious  malarial 
infection.  The  Malpighian  tufts  are  greatly  congested,  the  capillaries  being 
distended  with  blood,  some  of  them  having  ruptured,  thus  causing  hemorrhages 
with  Bowman's  capsule.  Many  of  these  capillaries  contain  free  plasmodia, 
round  or  oval  in  shape  and  generally  pigmented.  The  capillaries  also  contain 
a  small  number  of  infected  red  corpuscles,  free  pigment,  degenerated  plasmodia, 
and  phagocytic  cells.  The  number  of  plasmodia,  both  free  and  within  red 
cells,  is  very  much  smaller  than  in  sections  of  the  liver  or  spleen. 

The  epithelium  of  the  tubules  is  much  swollen  and  is  rapidly  proliferating 
while  the  protoplasm  of  the  cells  is  smoky  and  finely  granular  in  appearance, 
and  contains  in  many  instances  pigment  grains  of  a  yellowish  color.  One 
of  the  most  interesting  features  of  the  kidney  sections  is  the  occurrence  within 
the  tubules  of  collections  of  black  pigment  and  here  and  there  a  few  plasmodia. 
A  few  infected  red  cells  are  also  present  within  the  tubules.  The  intertubular 
capillaries  contain  numerous  free  pigmented  plasmodia,  infected  red  cells  and 
macrophages.  The  walls  of  the  capillaries  are  not  thickened.  The  amount 
of  pigment  present  in  the  kidney  is  very  slight  as  compared  with  that  present 
in  the  liver  and  spleen,  and  the  same  is  true  of  the  number  of  plasmodia. 

The  Brain. — The  changes  observed  in  the  sections  of  the  brain  may  be 
divided  into  those  occurring  within  the  capillaries  and  those  within  the  brain 
substance  proper.  The  small  capillaries  of  the  brain,  especially  those  of  the 
cortex,  are  crowded  with  pigmented,  free  plasmodia,  leucocytes  containing  pig- 
ment, and  in  some  places  by  small  collections  of  yellow  pigment.  The  infected 
capillaries  are  most  numerous  in  the  cortical  portion  of  the  brain,  but  they  are 
by  no  means  rare  in  the  medullary  portion.  The  pigment  within  the  capillaries 
is  generally  collected  in  irregular  masses,  is  brownish-black  in  color,  and,  in 
some  places,  entirely  occluded  the  lumen  of  the  capillary.  The  plasmodia 
present  in  the  capillaries  are  mostly  free,  small  in  size,  oval  or  round  in  shape, 
and  contain  pigment,  which  is  generally  collected  at  or  near  the  center  in  the 
form  of  a  few  small  grains  or  a  single  black  block.  It  is  remarkable  how  uni- 
form these  plasmodia  are  in  appearance  and  how  rarely  an  infected  red  cell  is 
observed.  In  some  places  the  capillaries  are  occluded  by  immense  macrophages 
containing  much  pigment  and  numerous  plasmodia. 

The  changes  occurring  within  the  substance  of  the  brain  consist  in  a  necro- 
sis of  the  protoplasm  of  some  of  the  cortical  cells,  as  is  evidenced  by  the  ir- 
regular staining  reactions  of  the  protoplasm  and  nucleus.  Sections  of  the 
heart,  lungs,  stomach,  and  intestines  were  not  examined  as  they  presented  no 
evidences  of  malarial  infection. 

The  above  autopsy  record  illustrates  the  common  findings  after  death 
from  pernicious  malaria,  but  much  greater  changes  are  often  observed,  changes 


l6o  THE    PATHOLOGY    OF    THE    MALARIAL   FEVERS. 

so  characteristic  that  a  glance  suffices  to  diagnose  the  cause  of  death,  while  in 
rare  instances  the  lesions  of  malaria  may  be  so  slight  as  to  be  of  little  service  in 
diagnosis. 

Literature  upon  the  Special  Pathology  of  the  Malarial  Fevers. 

i  S7  5—7  6.  Kelsch.  Contribution  a  l'anatomie  pathologique  des  maladies  palus- 
tres  endemiques.     Arch,  de  phys.  et  path.,  No.  5,  p.  6qo. 

1885.  Councilman  and  Abbott.  A  Contribution  to  the  Pathology  of  Malarial 
Fever.     Am.  Jour.  Med.  Sciences,  vol.  lxxxix,  p.  416. 

1893.      Dock.     Pernicious  Malarial  Fever.     Am.  Jour.  Med.  Sciences,  April,  p. 

379- 

1895.      Barker.     A    Study   of    Some    Fatal    Cases    of    Malarial    Fever.     Johns 

Hopkins  Hosp.  Reports,  vol.  v,  p.  221. 

1895.  Monti.     Atti.  d.  R.  Accad.  med.  d.  Roma,  series  II,  vol.  iii,  p.  249. 

1896.  Bignami.  Richerche  sulla  Anat.  Pathol,  della  Perniciosa.  Atti.  d.  R. 
Accad.  d.  med.  d.  Roma,  vol.  v,  series  ii. 

1897.  Guarnieri.  Richerche  sulla  alterazioni  della  retina  nella  infezione  acuta 
da  malaria.     Arch,  per  lesc.  med.,  xxi,  No.  i. 

1897.     Thayer.     Lectures  upon  the  Malarial  Fever.      New  York,  p.  211. 

1 90 1.      Ewing.     Contribution  to  the  Pathological  Anatomy  of  Malarial  Fever. 

Jour,  of  Exper.  Med.,  No.  5,  p.  119. 
1 90 1.     Craig,  C.  F.     The  Aestivo-autumnal  Fevers,  New  York,  p.  91. 


CHAPTER  III. 

[  The  Pathology  of  Latent  Malarial  Infections  and  of  Malarial  Cachexia. 

Pathology  of  Latent  Malarial  Infections. — By  a  latent  malarial  in- 
fection we  mean  a  malarial  infection  which  is  not  manifested  by  any  symptoms, 
and  in  which  an  examination  of  the  blood  may  or  may  not  show  the  presence 
of  the  plasmodia.  The  pathology  of  such  infections  has  received  but  little 
attention,  and  if  we  confine  the  term  "latent  infection"  only  to  those  cases  in 
which  no  symptoms  are  present  and  no  plasmodia  are  found  upon  repeated 
examinations  of  the  blood,  it  will  at  once  be  seen  why  the  pathology  of  this 
condition  has  not  been  investigated.  Such  cases  of  malarial  infection  will  only 
be  discovered  at  autopsy,  the  patient  having  died  from  some  other  disease,  and 
outside  of  the  tropics  and  the  more  malarial  regions  of  the  temperate  zones, 
such  cases  will  necessarily  be  very  rare.  In  this  chapter  I  shall  only  touch  upon 
the  pathology  of  those  cases  in  which  no  plasmodia  were  demonstrated  in  the 
blood  and  no  clinical  symptoms  of  malaria  were  detected  before  death. 

During  my  service  at  the  U.  S.  Army  General  Hospital  at  he  Presidio  of 
San  Francisco  I  observed  seven  cases  in  which  the  autopsy  showed  latent 
malarial  infection  in  which  before  death  no  symptoms  of  malaria  had  developed 
and  no  plasmodia  had  been  detected  in  the  peripheral  blood.  Three  of  these 
cases  were  benign  tertian  infections  and  four  aestivo-autumnal  infections  of  the 
tertian  type. 

Pathology  of  Latent  Tertian  Malaria. — The  pathologic  lesions  present 
were  confined  entirely  to  the  liver  and  spleen,  and  this  was  also  true  of  the 
aestivo-autumnal  infections.  In  numerous  cases  coming  to  autopsy  from 
other  diseases,  accompanied  by  a  latent  malarial  infection  in  which  the  plasmo- 
dia were  found  in  the  blood  before  death,  but  in  which  there  were  no  definite 
symptoms  of  malaria,  it  was  observed  that  the  chief  pathologic  lesions  of 
malaria  were  also  found  in  the  liver  and  spleen,  but  that  other  organs  presented 
slight  lesions.  Thus  it  will  be  seen  that  from  the  mildest  latent  infections  to 
the  severe  acute  infections  there  is  a  gradual  progress  in  the  pathological  lesions, 
first  manifested  in  the  liver  and  spleen  and  spreading,  according  to  the  extent 
and  severity  of  the  infection,  to  all  the  organs. 

The  Spleen. — In  these  latent  infections  the  most  marked  lesions  were 
always  present  in  the  spleen.  The  organ  in  the  tertian  infections  was  con- 
siderably enlarged  and  dark  bluish  in  color  externally,  the  capsule  smooth  and 
tense,  the  notches  distinct,  and  the  organ  somewhat  decreased  in  consistence. 
Upon  section  the  color  was  a  dark  browish-red,  but  did  not  present  that  browish 
or  black  color  found   n  well-marked  acute  infections;  this,  of  course,  is  easily 

TT  161 


1 62  THE    PATHOLOGY    OF    THE    MALARIAL    FEVERS. 

understood  from  the  fact  that  the  plasmodia  present  were  comparatively  few  in 
number  and  that  therefore  little  pigment  was  formed. 

Microscopically ',  the  sections  of  the  spleen  showed  intense  congestion  of  the 
splenic  sinuses,  together  with  pigmentation,  especially  marked  along  the  edges 
of  the  Malpighian  bodies  and  along  the  fibrous  trabecular  The  connective 
tissue  of  the  organ  was  not  increased.  The  cells  of  the  splenic  pulp  were  greatly 
increased  in  number  and  many  of  the  cells  showed  marked  division  of  the 
nucleus.     Many  also  were  pigmented  and  distorted  in  shape. 

The  splenic  sinuses  and  capillaries  showed  the  presence  of  numerous 
infected  red  cells  and  pigmented  leucocytes.  While  these  infected  cells  were 
not  nearly  as  numerous  as  in  acute  infections  or  as  in  more  advanced  latent 
infections,  still  they  were  sufficiently  numerous  as  to  be  very  noticeable.  The 
plasmodia  were  in  about  the  same  stage  of  development  in  each  case,  but  it 
so  happened  that  the  patients  had  died  at  such  a  period  that  the  entire  cycle  of 
the  tertian  plasmodium  within  the  human  body  could  be  worked  out  from 
examination  of  the  sections  of  the  spleen  from  these  cases.  As  far  as  could  be 
ascertained  the  plasmodia  presented  no  essential  difference  in  their  appearance 
from  those  found  within  the  red  cells  in  the  peripheral  circulation  during  an 
acute  infection.  The  sporulating  bodies  were  numerous  in  one  case,  the  seg- 
ments appearing,  however,  slightly  more  refractive  and  more  clearly  outlined 
than  when  found  in  the  peripheral  blood.  Their  staining  reactions  were 
exactly  the  same. 

The  chief  point  of  importance  in  the  pathology  of  these  cases  is  that  the 
entire  human  cycle  of  the  plasmodium  can  be  completed  within  the  spleen, 
thus  proving  conclusively  that  the  seat  of  the  initial  malarial  infection  is  in 
this  organ,  for  no  plasmcdia  could  be  demonstrated  in  the  blood  of  these  cases. 
While  this  has  been  the  opinion  of  nearly  all  authorities  for  several  years,  few 
observations  are  on  record  in  which,  as  in  these  cases,  no  malarial  symptoms 
or  plasmodia  could  be  determined  during  life,  but  the  entire  human  cycle  of 
the  organism  was  found  in  sections  of  the  spleen,  and  no  where  else  in  the  body. 

Besides  the  infected  red  cells,  numerous  leucocytes  were  observed  containing 
pigment  in  the  form  of  large  and  small  granules,  and  a  few  containing  malarial 
plasmodia.  Macrophages  were  also  present  containing  much  pigment  in 
large  blocks,  and  often  one  or  more  half  or  nearly  full-grown  plasmodia.  A 
small  amount  of  free  pigment  was  observed  lying  within  the  splenic  sinuses. 

The  Liver. — Macroscopically,  the  liver  did  not  differ  in  appearance  from 
that  of  a  normal  organ,  so  far  as  the  pathology  of  malaria  is  concerned.  Upon 
section  marked  venous  congestion  was  present  in  all  of  the  cases.  The  sections 
of  the  liver  showed  microscopically  a  few  pigmented  leucocytes  within  the 
capillaries,  some  of  the  leucocytes  containing  degenerated  plasmodia.  There 
was  but  little  pigment  present  in  the  organ,  most  of  it  being  within  leucocytes. 
No  macrophages  were  observed,  most  of  the  pigmented  leucocytes  being  of 
the  polynuclear  type.  A  very  careful  search  was  made  in  the  sections  of 
the  liver  for  infected  red  corpuscles,  but  in  no  one  of  the  cases  was  an  infected 


THE  PATHOLOGY  OF  THE  MALARIAL  FEVERS.  1 63 

red  corpuscle  observed.  It  will  thus  be  seen  that  the  lesions  in  these  latent 
cases  were  almost  entirely  confined  to  the  spleen,  the  liver  being  but  very  slightly 
involved. 

Pathology  of  Latent  Aestivo-autumnal  Malaria. — The  pathology 
of  latent  aestivo-autumnal  malarial  infections  differs  but  little  from  that  of 
tertian  infections  and  chiefly  in  the  type  of  the  plasmodia  present. 

The  Spleen.— Macroscopically,  the  spleen  appeared  much  as  the  spleen 
in  the  tertian  infections,  save  that  in  all  cases  it  was  not  as  much  enlarged  nor 
as  much  pigmented.  Upon  section  the  consistence  was  found  decreased,  the 
Malpighian  bodies  nearly  invisible,  the  color  a  dark  mahogany-red — in  one  case 
brown — the  substance  of  the  spleen  being  almost  diffluent  in  two  of  the  cases. 
Upon  microscopical  examination  the  same  changes  were  found  as  in  the  tertian 
latent  cases,  the  splenic  sinuses  being  congested,  the  cells  of  the  splenic  pulp 
increased  in  number  and  showing  marked  division  of  the  nucleus,  considerable 
pigmentation  present,  and  the  presence  of  infected  red  corpuscles  and  melan- 
iferous  leucocytes.  The  infected  red  cells  were  not  as  numerous  as  in  the  tertian 
latent  infections.  The  plasmodia  observed  within  the  red  corpuscles  were 
almost  uniformly  in  one  stage  of  growth,  but  in  the  sections  of  the  spleen  from 
the  four  cases  all  stages  in  the  human  life  cycle  of  the  aestivo-autumnal  Plasmo- 
dium (tertian)  could  be  observed.  The  younger  forms  were  similar  in  appear- 
ance to  the  young  forms  observed  in  the  peripheral  blood,  being  small,  hyaline 
rings,  presenting  in  smears  from  the  spleen,  marked  amoeboid  motion.  The 
older  plasmodia  were  disk-shaped  or  ring-like,  and  contained  more  or  less 
pigment  in  the  form  of  very  fine  reddish-brown  granules,  the  pigment  being 
very  slightly  motile.  In  one  case  numerous  sporulating  bodies  were  observed, 
the  sporulation  always  occurring  within  the  red  cell.  The  segments  varied 
in  number,  the  largest  number  counted  being  24,  the  smallest  12.  A  peculiarity 
about  the  segments  was  that  each  appeared  to  present  the  "ring-form"  which 
is  usually  found  in  the  red  cell  at  the  earliest  stage  of  infection.  This  appear- 
ance was  so  distinct  that  the  infected  corpuscle  appeared  to  be  filled  with  minute 
" rings."  The  pigment  in  the  sporulating  bodies  was  collected  either  at  the 
center  or  to  one  side,  and  none  of  the  segments  contained  any  pigment. 

No  crescents  were  observed  in  the  sections  of  the  spleen  from  any  of  the 
cases.  Numerous  pigmented  leucocytes  were  observed  and  macrophages 
containing  much  pigment  and  one  or  two  plasmodia.  Considerable  free  pig- 
ment was  present  in  the  same  localities  as  noted  in  the  tertian  cases. 

The  Liver. — The  pathologic  changes  in  the  liver  were  similar  to  those 
observed  in  the  tertian  latent  cases.  No  infected  red  cells  were  found,  although 
a  considerable  number  of  melaniferous  leucocytes  were  observed,  together 
with  some  free  pigment. 

The  chief  point  of  value  in  the  pathology  of  latent  malaria  is  the  demonstra- 
tion that  the  malarial  plasmodia  are  capable  of  undergoing  their  entire  human 
life  cycle  within  the  spleen,  thus  proving  the  time-honored  theory  that  the 
spleen  is  the  seat  of  all  malarial  infections.     Most  of  these  cases  were  present 


164  THE  PATHOLOGY  OF  THE  MALARIAL  FEVERS. 

in  the  hospital  for  several  weeks;  repeated  blood  examinations  were  made; 
they  were  carefully  studied  clinically,  and  in  none  of  them  was  malarial  infection 
suspected.  It  is  obvious  that  puncture  of  the  spleen  would  probably  have 
resulted  in  the  discovery  of  the  malarial  infection  in  these  cases,  but  this 
procedure  is  dangerous,  even  in  experienced  hands,  and  is  certainly  not  advisable 
as  a  routine  measure. 

The  Pathology  of  Malarial  Cachexia. — Since  the  separation  of  kala-azar 
and  malaria  upon  etiological  and  pathological  grounds,  the  pathology  of 
malarial  cachexia  is  much  better  understood  than  when  these  two  infections 
were  confused.  Almost  every  writer  upon  malaria  describe  marked  pathological 
lesions  in  chronic  malarial  poisoning,  but  it  is  more  than  probable  that  many 
of  them  are  due  to  complicating  diseases  rather  than  to  the  malarial  infection. 

The  Blood. — In  the  majority  of  patients  suffering  from  repeated  attacks 
of  malaria,  in  whom  a  cachectic  condition  has  developed,  there  is  present  a 
greater  or  less  degree  of  anemia,  the  red  cells  seldom  numbering  over  3,000,000 
per  cu.  mm.  and  often  not  over  1,500,000  per  cubic  millimeter.  The  haemo- 
globin is  proportionately  reduced,  and  there  is  often  an  increase  in  the  large 
mononuclear  leucocytes.  In  severe  cases  nucleated  red  cells  may  be  present, 
and  poikilocytosis  is  often  marked. 

From  their  researches  Dionisi  and  Bignami  have  separated  four  types  of 
postmalarial  anaemia,  as  follows: 

"1.  Anaemiae  in  which  the  examination  of  the  blood  shows  alterations 
similar  to  those  observed  in  secondary  anaemia,  from  which  they  differ  only  in 
that  the  leucocytes  are  diminished  in  number.  The  greater  part  of  these  cases 
go  on  to  recovery;  a  few,  without  any  further  change  in  the  haematological  situ- 
ation, pursue  a  fatal  course. 

"2.  Anaemiae  in  which  the  examination  of  the  blood  shows  alterations  simi- 
lar to  those  seen  in  pernicious  anaemia — presence  of  gigantoblasts.  These  cases 
end  fatally. 

"3.  Anaemiae  which  are  progressive,  as  the  result  of  compensation  by  the 
marrow  for  losses  brought  about  by  the  infection.  At  autopsy  the  marrow  of 
the  long  bones  is  found  to  be  wholly  yellow,  while  the  marrow  of  the  flat  bones 
is  also  poor  in  nucleated  red  cells. 

"4.  Chronic  anaemiae  of  the  cachectic,  which  differ  from  the  above-men- 
tioned types  by  clinical  and  anatomical  characters,  in  that  the  special  symptoms 
of  malarial  cachexia  prevail,  while  one  observed  postmortem,  a  sort  of  sclerosis 
of  the  bone-marrow." 

I  agree  fully  with  Dionisi  and  Bignami  regarding  the  forms  of  anaemia 
following  acute  malaria,  and  have  observed  very  severe  anaemiae  of  the  secondary 
type  frequently  A  pernicious  anaemia  following  malaria  has,  in  my  ex- 
perience, been  very  rare,  only  one  case  being  observed  in  over  5,000  patients. 

Aside  from  the  blood,  the  chief  pathological  lesions  in  malarial  cachexia 
occur  in  the  spleen,  the  liver,  and  the  bone-marrow. 

The  Spleen. — In  most  instances  the  spleen  is  greatly  enlarged,  sometimes 
weighing  several  pounds;  is  generally  greatly  pigmented;  the  capsule  more  or 


THE    PATHOLOGY    OF    THE    MALARIAL    FEVERS.  165 

less  roughened  by  adhesions;  the  color  of  the  cut  surface  being  slate,  brown,  or 
black;  the  Malpighian  corpuscles  standing  out  as  almost  white  areas.  The  con- 
nective tissue  of  the  organ  is  often  increased  macroscopically.  Microscopically, 
the  lesions  consist  in  marked  enlargement  and  fibrosis  of  Malpighian  cor- 
puscles, increased  connective  tissue  along  the  trabeculae,  which  encroaches  upon 
the  parenchyma  in  places,  enormous  distention  of  the  splenic  sinuses,  and  the 
replacement  of  the  splenic  pulp  by  connective  tissue  containing  large  and  small 
round  cells.  Pigmentation  is  very  marked,  the  pigment  being  collected  about 
the  Malpighian  corpuscles  and  along  the  fibrous  trabeculae  and  in  the  walls  of 
the  blood-vessels.  Hyperplasia  of  the  cells  of  the  splenic  pulp  occurs  in  places, 
especially  about  the  enlarged  follicles. 

The  Liver. — The  liver  may  be  enlarged  or  it  may  be  atrophied,  according 
to  the  length  of  time  the  cachexia  has  lasted.  The  perilobular  connective 
tissue  may  be  increased  and  there  may  be  a  hyperplasia  of  the  liver  parenchyma. 
Severe  chronic  venous  congestion  may  be  present  and  angiomata  may  be 
formed  in  the  liver  substance.  The  pigmentation  is  excessive  at  times,  while 
in  those  patients  who  have  suffered  from  cachexia  for  years  the  malarial  pig- 
mentation may  have  entirely  disappeared.  In  greatly  pigmented  livers  the 
outline  of  the  lobules  may  be  distinctly  traced  by  the  deposit  of  pigment,  much 
of  the  pigment  being  extravascular. 

The  question  as  to  the  occurrence  of  cirrhosis  of  the  liver  as  the  result  of 
prolonged  malaria  infection  is  still  sub  fudice.  While  in  many  instances  the 
liver  in  cachetics  is  atrophic,  inquiry  will  generally  develop  the  fact  that  the 
atrophy  is  as  apt  to  be  due  to  one  of  several  causes  as  to  the  malarial  infection. 
I  am  inclined  to  believe  that  in  susceptible  individuals  severe  and  continued 
malarial  infection  may  produce  cirrhosis  of  the  liver,  but  such  cases  are  very 
rare,  and  I  have  never  observed  one  in  which  the  cirrhosis  of  the  liver  could  not 
have  been  attributed  to  other  causes. 

The  Bone-marrow. — The  changes  in  the  bone-marrow  are  due  princi- 
pally to  the  anaemia  produced  by  repeated  attacks  of  malaria.  The  marrow  of 
the  long  bones  is  generally  red  in  color  and  there  is  a  marked  increase  in  the 
consistence.  The  fatty  tissue  has  been  replaced  by  vascular  medullary  tissue, 
composed  of  large  cells  showing  mitotic  nuclei,  lymphoid  cells,  giant  cells,  and 
normoblasts.  Pigmentation  may  be  almost  absent  even  when  the  other  viscera 
are  markedly  pigmented.  In  long-continued  cases  the  nucleated  cells  are 
rare,  and  in  some  cases  the  microscopical  lesions  are  those  of  pernicious 
anaemia. 

Forms  of  Degeneration. — In  the  liver,  spleen,  and  kidney,  cloudy  swelling 
and  fatty  degeneration  of  the  cells  of  the  parenchyma  is  noted  and  amyloid 
degeneration  is  not  uncommon.  While  this  change  is  not  characteristic 
of  malaria,  it  occurs  so  frequently  in  malarial  cachexia  as  to  be  of  importance. 
In  the  kidneys  it  is  most  usually  observed,  affecting  the  smaller  blood-vessels 
and  the  walls  of  the  tubules.  It  also  occurs  in  the  intestine  in  the  vessels  of  the 
villi   and  in  the  spleen,  affecting  chiefly  the  capillaries  of  the  follicles.     The 


l66  THE    PATHOLOGY    OF    THE    MALARIAL    FEYERS. 

liver  is  not  as  often  the  seat  of  amyloid  degeneration  as  in  other  diseases,  the 
condition  being  most  noticeable  at  the  periphery  of  the  lobules. 

The  changes  in  the  other  viscera  are  not  of  special  interest.  The  heart 
muscle  is  often  flabby  and  below  normal  in  thickness,  while  the  anaemia  present 
renders  it  pale  in  color.  Fatty  degeneration  of  the  heart  muscle  is  not  com- 
monly observed,  and  pigmentation  is  generally  absent.  The  intestinal  canal 
shows  no  changes  of  importance  except  amyloid  degeneration  in  a  small  propor- 
tion of  the  cases.     The  lungs  show  no  lesions  characteristic  of  malarial  cachexia. 

The  enlargement  of  the  spleen,  so  long  relied  upon  as  indicative  of  chronic 
malarial  infection,  can  no  longer  be  held  as  of  much  assistance  in  diagnosis  in 
regions  where  kala-azar  is  prevalent,  as  in  such  regions  the  spleen  index  is 
most  unreliable  as  showing  the  proportion  of  malarial  infections.  It  is  probable 
that  careful  study  of  the  fevers  occurring  in  the  tropics  will  demonstrate  that 
enlargement  of  the  spleen  is  common  to  many  of  them. 

Literature  upon  the  Pathology  of  Latent  Malarial  Infection  and  Malarial  Cachexia. 

Pathology  of  Latent   Malaria  Infection. 

1903.     Craig,  C.  F.     The  Pathology  of  Latent   Malarial  Infection  as  Observed 
at  Autopsy.      American  Medicine,  vol.  vi,  No.  4,  p.  145. 

Pathology  of   Malarial  Cachexia. 

The   monographs  upon  malaria  which  have  been  referred  to  in  previous 
chapters,  especially  those  of  Thayer,  Marchiafava  and  Bignami,  Ziemann,    and 
Mannaberg. 
1892-3.      Bignami.      Studi   sull'    anatomia   patologica   della   infezione   malarica 

chronica.      Bull.  dell.  R.  accad.  med.  d.  Roma,  xix,  f.  ii,  p.  186. 
1894.      Bignami   and   Dionisi.      Die  Postmalarischen   und   die   experimentellen 

chronischen  toxischen  Anaemien.      Cent.  f.  allg.  path,  anat.,  v,  No.  10,  p. 

432- 


PART  III. 

THE   SYMPTOMATOLOGY  AND   CLINICAL  VARIETIES    OF   THE 

MALARIAL  FEVERS. 


CHAPTER  I. 

Clinical  Classification;  Tertian  Malarial  Fever;  Quartan  Malarial  Fever; 
Aestivo-autumnal  Malaria;  Analysis  of  Symptoms;  Examination  of  the  Blood. 

Clinical  Classification. — It  is  often  extremely  difficult  to  classify  the 
malarial  fevers  from  a  clinical  standpoint.  A  division  of  these  infections 
into  intermittent,  remittent,  and  continuous  fevers,  so  often  followed,  is  useful, 
but  is  at  best  a  rough  classification  which  does  not  indicate  disease  entities, 
and  is  confusing  in  many  ways.  It  may  be  stated  that  any  malarial  fever  may 
be  intermittent,  remittent,  or  continuous.  For  instance,  while  a  single  tertian 
infection  is  undoubtedly  intermittent  in  type,  we  can  conceive  of  a  tertian 
infection  in  which  several  groups  of  plasmodia  sporulating  at  various  periods 
may  give  rise  to  a  remittent  or  even  continuous  temperature  curve,  and  in 
practice  benign  tertian  infections  remittent  in  type  are  not  so  very  uncommon. 
The  same  holds  true  of  quartan  infections  and  especially  of  the  aestivo-autumnal 
fevers.  It  is  also  a  fact  that  infection  with  a  single  generation  of  any  one  of 
the  malarial  plasmodia  will  result  in  an  intermittent  fever"  In  other  words, 
all  malarial  infections  are  intermittent  in  character  and  only  become  remittent 
or  continuous  when  more  than  one  generation  of  the  plasmodium  matures 
at  different  intervals  of  time,  or  when  the  typical  character  of  the  temperature 
curve  is  disturbed  by  inadequate  treatment  or  by  the  natural  resisting  powers 
of  the  individual.  While  the  term  "remittent  malaria"  is  generally  applied  to 
infections  produced  by  the  aestivo-autumnal  plasmodia,  the  name  is  a  misnomer, 
as  the  aestivo-autumnal  infections  are  as  truly  intermittent  as  are  the  tertian 
and  quartan.  For  this  reason,  I  believe  that  classification  should  rest  upon 
etiology  in  these  infections  and  that  clinical  classification  resting  upon  any  other 
basis  is  unscientific  and  inevitably  leads  to  confusion  and  a  loose  method  of 
diagnosis.  It  is  of  the  greatest  importance  in  the  treatment  of  malaria  that 
we  know  to  which  species  of  plasmodium  the  fever  is  due,  and  this  we  can  only 
know,  in  most  instances,  by  an  examination  of  the  blood.  A  classification 
based  upon  the  character  of  the  temperature  curve  is  very  misleading  and  tends 
to  lead  to  carelessness  in  making  the  blood  examination  or  to  neglect  of  that 
most  important  procedure.  Stastistics  of  the  type  of  malaria  present  in  any 
locality  based  entirely  upon  the  character  of  the  temperature  curve  are  worse 
than  useless  and  should  receive  but  little  consideration  in  the  study  of  malarial 
endemicity. 

The  following  classification  is  adopted  in  this  work,  as  it  would  appear 
to  be  the  best  from  both  a  clinical  and  etiological  point  of  view: 

i.  Tertian  malaria,  due  to  Plasmodium  vivax. 

169 


170  THE    SYMPTOMATOLOGY    OF    THE    MALARIAL    FEVERS. 

2.  Quartan  malaria,  due  to  Plasmodium  malariae. 

3.  Tertian    aestivo-autumnal    malaria,    due    to  Plasmodium    falciparum. 

4.  Quotidian  aestivo-autumnal  malaria,  due  to  Plasmodium  falciparum 
quotidanum. 

As  I  have  already  stated,  I  hold  with  Marchiafava  and  Bignami  and  others 
that  there  are  two  distinct  types  of  aestivo-autumnal  infection,  both  from 
a  clinical  and  etiological  standpoint,  and  I  have  already  considered  the  morpho- 
logical differences  between  the  two  types  or  species  of  plasmodia,  but  we  do 
not  have  to  rely  solely  upon  such  differences  in  distinguishing  these  fevers, 
for  both  varieties  are  distinct  clinically  in  uncomplicated  cases.  I  am  aware 
that  many  observers  have  failed  to  recognize  two  forms  of  aestivo-autumnal 
malaria,  but  I  am  sure  that  any  unprejudiced  observer  will  admit  the  existence 
of  these  two  forms  of  infection,  if  he  studies  uncomplicated  cases  of  aestivo- 
autumnal  fever  in  which  quinine  has  not  been  given  and  in  regions  where  these 
infections  are  endemic. 

As  to  the  relative  frequency  of  these  two  forms  of  malaria  it  is  undoubtedly 
true  that  the  tertian  aestivo-autumnal  infection  is  altogether  the  most  frequent. 
From  the  data  I  possess,  comprising  several  thousand  cases  of  aestivo-autumnal 
fever,  the  tertian  plasmodium  was  found  in  about  75  per  cent,  of  the  cases. 
.  The  impression  which  prevails  among  many  physicians,  that  a  remittent 
temperature  curve  is  characteristic  of  all  aestivo-autumnal  infections,  is  a  false 
one,  for  irregularity  or  remittence  is  by  no  means  confined  to  the  aestivo- 
autumnal  infections,  which,  if  uncomplicated,  are  as  truly  intermittent  as  are 
either  the  benign  tertian  or  quartan  fevers.  While  it  is  true  that  irregularities 
of  temperature  are  more  apt  to  occur  in  aestivo-autumnal  cases,  because  they 
are  more  resistant  to  treatment  and  are  more  commonly  produced  by  multiple 
groups  of  plasmodia,  it  is  not  true  that  a  remittent  temperature  curve  is 
characteristic  of  them  and  that  a  diagnosis  can  be  based  upon  such  remittency. 
Any  malarial  fever  may  become  irregular  or  remittent,  from  a  multitude  of 
causes,  one  of  the  chief  of  which  is  the  unscientific  use  of  quinine. 

Clinically,  all  aestivo-autumnal  fevers  should  be  classed  as  severe  forms 
of  malarial  fever,  in  contradistinction  to  the  tertian  and  quartan  types  which 
are  classed  as  mild  or  benign  types  of  malarial  infection.  This  classification 
of  the  aestivo-autumnal  fevers  as  severe  forms  is  of  great  importance.  While, 
of  course,  comparatively  few  aestivo-autumnal  infections  result  fatally,  and 
while  most  are  readily  amenable  to  proper  treatment  and  many  are  cured 
spontaneously,  the  fact  remains  that  almost  all  of  the  pernicious  malarial 
fevers  are  caused  by  the  aestivo-autumnal  plasmodia,  and  every  case  showing 
the  presence  in  the  blocd  of  these  plasmodia  should  be  considered  as  serious 
in  nature  and  treated  accordingly. 

The  old  idea  that  pernicious  malaria  is  due  to  a  particular  species  of 
Plasmodium  has  long  ago  been  abandoned,  and  we  now  have  upon  record 
fatal  cases  of  malaria  due  to  all  four  species  of  plasmodia,  although  most 
fatal  infections  have  been  due  to  the  tertian  aestivo-autumnal  parasite.     In 


THE    SYMPTOMATOLOGY    OF    THE    MALARIAL    FEVERS.  171 

my  own  experience  this  species  has  occurred  most  frequently  in  fatal  infections, 
but  the  quotidian  plasmodium  occurs  more  frequently  than  either  the  benign 
tertian  or  the  quartan  plasmodia.  The  aestivo-autumnal  plasmodia  occurring 
in  the  blood  in  fatal  infections  differ  in  no  way  from  those  occurring  in  aestivo- 
autumnal  infections  in  general,  and  it  is  probably  the  susceptibility  of  the 
patient  and  the  number  of  the  plasmodia  present  which  determines  the  pernicious 
character  of  the  attack  rather  than  the  species  of  aestivo-autumnal  plasmodium 
present. 

Some  authorities  have  striven  to  establish  a  class  of  malarial  infections 
characterized  by  long  intervals  between  the  paroxysms,  the  so-called  "long- 
interval  fevers,"  in  which  six,  eight,  or  even  ten  days  elapse  between  the  attacks 
of  fever.  Such  a  classification  is  not  consistent  with  what  we  know  of  the 
plasmodia  causing  the  different  types  of  malaria,  and  is  undeserving  of  con- 
sideration. Such  cases  are  simply  relapses  of  a  malarial  infection,  and  are  as 
apt  to  be  due  to  the  tertian  or  quartan  plasmodium  as  to  either  of  the  aestivo- 
autumnal  plasmodia.  In  rare  instances  a  case  is  observed  which  apparently 
shows  some  such  regularity,  but  the  resemblance  is  only  apparent,  for  an  exami- 
nation of  the  blood  will  demonstrate  that  the  cycle  of  development  of  the 
plasmodium  causing  it  is  completed  as  usual,  although  clinical  symptoms  may 
be  absent  or  atypical  at  certain  times;  in  other  words,  the  infection  is  latent. 

Symptoms  of  Tertian  Malarial  Fever. — The  paroxysms  of  fever  in 
benign  tertian  malaria  occur  every  forty-eight  hours  and  are  initiated  by  the 
sporulation  of  the  tertian  plasmodium  or  Plasmodium  vivax.  The  time  of 
the  onset  of  the  paroxysm  can  be  accurately  judged  by  the  stage  of  growth  of  the 
organism  as  observed  in  the  peripheral  blood.  The  onset  of  the  paroxysm 
always  occurs  during  the  segmentation  of  the  plasmodium,  and  quotidian 
paroxysms  are  caused  by  double  infections  with  the  tertian  plasmodium. 

This,  the  most  common  and  mildest  form  of  malarial  fever,  occurs  in  both 
temperate  and  tropical  countries,  being  the  most  common  type  in  the  tem- 
perate zones,  and  in  certain  localities  in  the  tropics.  Of  2,803  cases  of  malaria 
observed  by  myself  in  soldiers  returning  from  the  Philippines  and  from  Cuba, 
839  suffered  from  tertian  malaria,  of  which  220  were  double  tertian  infections. 
In  Baltimore,  of  542  cases  of  malaria  observed  by  Thayer  and  Hewetson,  338 
were  tertian  infections,  while  of  71  cases  studied  by  Mannaberg  in  Vienna  all 
but  10  were  infected  with  this  organism.  In  uncomplicated  cases  this  type  of 
malaria  presents  a  typical  temperature  curve,  showing  in  single  infections  a  rise 
of  temperature  every  second  day;  in  double  infections,  a  rise  of  temperature 
every  day;  while  in  infections  with  numerous  groups  of  tertian  plasmodia  there 
may  be  a  remittent  or  sub-continued  temperature  curve.  In  cases  presenting 
quotidian  paroxysms  it  is  often  possible  to  destroy  one  group  of  parasites  by 
small  doses  of  quinine,  and  when  this  is  done  the  regular  tertian  paroxysm  will 
reappear. 

The  paroxysm,  when  typical,  is  divided  into  three  stages,  chill,  fever,  and 
sweating.     The  prodromal  symptoms  are  generally  malaise,  loss  of  appetite,. and 


172        THE  SYMPTOMATOLOGY  OF  THE  MALARIAL  FEVERS. 

more  or  less  dull  headache  and  slight  aching  in  the  extremities.  After  these 
symptoms  have  persisted  for  a  few  days  (and  during  this  period  the  plasmodia 
may  often  be  observed  in  the  peripheral  blood  in  small  numbers)  the  patient  is 
seized  with  a  severe  chill,  but  although  he  feels  extremely  cold  the  temperature 
continues  to  rise,  and  at  the  acme  of  the  chill  has  reached  1030,  1040,  or  even 
1060  F.  The  chill  is  immediately  followed  by  a  pronounced  sense  of  heat,  and 
in  a  short  period  of.  time  the  patient  will  complain  as  bitterly  of  this  as  he  pre- 
viously had  of  the  cold.  During  the  stage  of  fever,  delirium  may  be  present  and 
there  is  generally  severe  headache.  During  the  onset  of  the  chill,  nausea  and 
vomiting  are  common,  but  they  do  not  persist,  as  a  rule,  during  the  stage  of 
fever.  After  the  fever  has  lasted  for  a  few  hours,  it  rapidly  declines  to  normal, 
accompanied  by  very  severe  sweating,  the  entire  skin  being  bedewed  with 
moisture,  often  so  pronounced  that  the  bed-clothing  is  saturated.  The  follow- 
ing detailed  description  is  true  of  most  tertian  malarial  paroxysms: 

The  Cold  Stage  or  Chill. — As  I  have  mentioned,  there  are  generally 
some  prodromal  symptoms  of  the  approaching  malarial  chill  as  evidenced  by 
yawning,  a  general  sense  of  discomfort,  headache,  and  often  nausea  and  vomit- 
ing. The  feeling  of  cold  usually  commences  at  the  feet  and  gradually  pro- 
gresses upward,  although  very  often  the  first  chilly  sensations  are  felt  along  the 
spine.  In  tertian  infections  the  chill  is  severe,  the  patient  shaking  very  vigor- 
ously, but  it  is  not  so  severe  as  in  most  quartan  infections.  In  certain  mild 
cases  the  chill  may  be  absent,  the  patient  complaining  only  of  chilly  sensations. 
The  facial  expression  of  the  patient  during  the  chill  is  one  of  cyanosis,  the  lips 
being  blue  and  the  skin  bluish-red  in  color.  The  extremities  are  cyanotic  and 
the  skin  presents  the  well-known  condition  characterized  as  "goose-flesh." 
The  pulse  is  rapid,  generally  rather  diminished  in  volume  and  often  irregular. 
Headache  is  very  often  intense.  During  the  chill  the  temperature  rises  very 
rapidly,  reaching  1040  F.  or  more  in  severe  cases,  but  careful  examination  will 
demonstrate  that  the  temperature  had  begun  to  rise  before  the  onset  of  the  chill. 
The  urine  is  increased  in  quantity  and  decreased  in  specific  gravity.  The 
duration  of  this  stage  varies  from  an  hour  to  two  hours  in  the  most  serious 
cases. 

The  Hot  Stage. — At  the  beginning  of  the  hot  stage  the  patient  complains 
of  flushes  of  heat,  rapidly  succeeded  by  cold  sensations.  Soon  the  sensations 
of  cold  are  entirely  lost  and  the  patient  complains  bitterly  of  the  intense  heat 
due  to  the  high  temperature.  The  facial  appearance  is  that  of  intense  con- 
gestion, the  conjunctivae  being  injected,  and  the  entire  surface  of  the  body 
reddened,  the  congestion  being  especially  marked  in  the  hands.  The  pulse 
is  full,  bounding,  and  often  dicrotic.  The  respirations  are  rapid  and  hurried, 
and  there  may  be  a  slight  cough  due  to  congestion  of  the  lungs.  The  headache 
increases  and  may  be  very  intense  and  of  a  throbbing  character. 

In  the  mild  tertian  attacks  there  are  no  nervous  symptoms  present  beyond 
a  severe  headache,  but  in  the  severe  cases  there  may  be  marked  delirium  or  a 
drowsy  condition  merging  into   semi-coma,   or  even  coma.     This  condition 


THE    SYMPTOMATOLOGY    OF    THE    MALARIAL   FEVERS.  1 73 

is  almost  always  present  in  those  rare  cases  of  tertian  fever  which  become 
pernicious. 

The  chief  cymptoms  complained  of  by  the  patient  during  the  hot  stage  are 
the  intense  heat  of  the  fever  and  the  headache.  The  temperature  may  reach  its 
highest  point  during  this  stage,  but  very  often  it  is  highest  at  the  end  of  the  cold 
stage.  It  is  not  uncommon  during  the  hot  stage  to  observe  skin  eruptions. 
Herpes  is  very  frequently  seen,  especially  about  the  lips,  and  urticaria  and  a 
general  erythema  not  infrequently  occur.  These  eruptions  sometimes  lead  to  a 
suspicion  of  some  eruptive  disease  being  the  cause  of  the  chill.  Herpes  of  the 
penis  may  occur  during  the  hot  stage  of  the  paroxysm  or  may  develop  later.  The 
duration  of  this  stage  varies  from  four  to  six  hours,  but  may  be  shorter  or  longer. 

The  Sweating  Stage. — As  the  fever  begins  to  decline,  it  will  be  noticed 
that  the  perspiration  appears  first  upon  the  forehead  and  face,  and  the  patient 
at  once  begins  to  feel  better,  the  decrease  in  the  unpleasant  symptoms  being 
proportionate  to  the  severity  of  the  sweating.  Commencing,  as  has  been  said, 
on  the  face,  the  perspiration  rapidly  involves  the  entire  body  and  is  often  so 
severe  that  water  may  be  seen  trickling  from  the  skin  of  the  arms,  thighs,  and 
legs.  The  sweating  stage  lasts,  as  a  rule,  from  two  to  three  hours,  at  the  end 
of  which  time  the  temperature  has  declined  to  normal,  all  of  the  unpleasant 
symptoms  have  disappeared,  and  the  patient  falls  into  a  sleep  which  may 
last  for  several  hours.  As  a  rule,  the  temperature  goes  somewhat  below  normal 
and  the  decline,  if  rapid,  as  it  often  is,  is  accompanied  by  considerable  weakness 
of  the  circulation,  the  pulse  being  slow  and  of  low  tension.  In  very  rare  cases 
this  stage  may  be  accompanied  by  collapse  and  death.  During  the  sweating 
stage  the  urine  may  be  increased  in  amount. 

The  average  duration  of  the  entire  tertian  paroxysm  is  from  eleven  to 
fourteen  hours,  but  it  should  be  remembered  that  there  are  paroxysms  so 
slight  as  to  be  hardly  recognized,  especially  in  children,  while,  on  the  other 
hand,  the  length  of  the  paroxysm  may  be  prolonged  to  twenty-four  hours. 
In  young  children  the  onset  of  the  malarial  paroxysm  is  often  accompanied 
by  convulsions.  (Chart  A.) 

Physical  examination  of  the  patient  will  often  show  an  enlarged  and 
tender  spleen,  but  this  sign  cannot  be  relied  upon  except  in  those  cases  which 
have  had  severe  and  repeated  infections.  An  enlarged  and  tender  spleen 
occurs  too  frequently  in  other  acute  infections  to  be  of  more  than  confirmative 
evidence  in  the  diagnosis  of  malaria.  Albuminuria  is  present  in  a  considerable 
proportion  of  the  cases  of  tertian  infection.  Of  over  1,000  cases  of  tertian 
infection  personally  observed  by  the  writer  nearly  46  per  cent,  showed  albumin 
in  the  urine,  and  it  is  probable  that  a  careful  examination  of  the  urine  in  all 
such  cases  would  result  in  showing  a  larger  percentage  than  this.  Hyaline  and 
granular  casts  are  found  in  the  urine  in  the  most  severe  cases,  but  not  as  fre- 
quently as  in  the  aestivo-autumnal  infections.  Polyuria  is  very  frequently 
observed  immediately  following  the  paroxysm,  and  it  may  persist  for  days  and 
even  weeks. 


m 


THE    SYMPTOMATOLOGY   OF    THE    MALARIAL    FEVERS. 


U 


THE    SYMPTOMATOLOGY    OF    THE    MALARIAL    FEVERS.  1 75 

Symptoms  of  Quartan  Malarial  Fever. — The  symptoms  of  quartan 
malarial  infection  are  very  similar  to  those  of  tertian  infections,  although  they 
are  generally  more  severe  in  character. 

Frequency  of  Quartan  Infections. — This  is  the  most  rare  form  of 
malarial  infection,  being  absent  in  many  malarial  localities,  and  occurring 
very  rarely  in  others,  while  in  some  regions  it  is  the  prevailing  type  of  infection. 
It  is  probably  most  common  in  temperate  regions,  but  is  not  infrequently 
observed  in  the  tropics  together  with  aestivo-autumnal  infections.  The 
following  table  illustrates  the  relative  frequency  of  this  type  as  observed  in 
different  localities: 


No.  of  cases 

Quartan 

Observer.                       observed. 

infections. 

Maillot,  in  Algeria,                  233& 

26 

Finot,  in  Blida,                         421 1 

2  1 

Laveran,  in  Algiers,                  311 

7 

Thayer  and  Hewetson,  in 

Baltimore,  U.  S.  A.,           1680 

i5 

Griesinger,  in  Tubingen,          414 

3 

Mannaberg,  in  Vienna,             144 

8 

In  my  own  experience,  comprising  over  5,000  cases  of  malaria  in  which  the 
Plasmodia  were  demonstrated  in  the  blood,  only  26  cases  of  quartan  infection 
were  observed.  Practically  all  of  the  cases  were  in  soldiers  returning  from  the 
Philippines  and  from  Cuba,  where  they  had  contracted  their  infection.  The 
percentage  of  quartan  infection  in  the  Philippine  Islands  is  higher,  however, 
than  in  many  other  tropical  countries,  as  is  shown  by  the  fact  that  Koch  only 
observed  one  case  of  this  infection  in  tropical  Africa  and  Zieman  reports  its 
absence  from  Kamerun,  while  I  observed  18  cases  in  the  Philippines  in  the 
course  of  about  twelve  months.  In  certain  regions  in  Italy  this  type  of  infection 
is  the  prevailing  one,  tertian  and  aestivo-autumnal  infections  being  almost 
unknown. 

In  most  localities  in  the  temperate  zones  quartan  infections  occur  most 
frequently  in  the  late  summer  and  during  the  autumn  months,  but  in  the 
tropics  they  occur  at  more  irregular  intervals  which  vary  with  the  time  of  the 
rainy  season,  these  infections  appearing  several  weeks  after  the  cessation  of  the 
rains  or,  in  other  words,  toward  the  latter  part  of  the  malarial  season 

The  Symptoms. — The  paroxysms  of  quartan  malaria  are  characterized 
by  their  regularity  in  uncomplicated  infections,  the  febrile  attacks  occurring 
at  the  end  of  every  72  hours,  but,  here  again,  we  may  have  double  infections, 
in  which  the  attacks  occur  upon  two  days  in  succession,  with  an  afebrile  day 
interposed,  or  triple  infections,  in  which  the  attacks  occur  daily.  Double  and 
triple  infections  are  comparatively  rare.  Mannaberg  saw  two  cases  of  double 
quartan,  and  Thayer  and  Hewetson  three  cases  of  triple  quartan.  I  have 
never  seen  a  triple  quartan  infection  and  only  one  double  infection.  Irregular 
and  sub-continued  quartan  infections  are  rarely  observed,  though  such  cases 
have  been  described  by  Antolisei  and  Feletti. 


176  THE    SYMPTOMATOLOGY    OF    THE    MALARIAL    FEVERS. 

As  in  tertian  infections  the  febrile  paroxysm  in  quartan  malaria  corresponds 
with  the  sporulation  of  the  quartan  parasite,  of  Plasmodium  malariae,  and  the 
time  of  the  occurrence  of  the  paroxysm  may  be  accurately  foretold  by  the 
stage  of  the  development  of  the  plasmodia  in  the  peripheral  blood. 

The  symptoms  observed  during  a  quartan  paroxysm  are  so  similar  to  those 
already  described  in  tertian  infections  that  a  detailed  account  of  them  is  not 
necessary.  There  are  the  same  stages  of  chill,  fever,  and  sweating  as  are  seen 
in  the  tertian  infections,  but,  as  a  rule,  the  symptoms  are  more  severe  and 
pernicious  attacks  are  more  common.  The  nervous  symptoms  especially 
are  apt  to  be  more  pronounced,  and  slight  delirium  is  very  common. 
(Chart  B.) 

The  quartan  paroxysm  is  not  as  prolonged  as  is  the  tertian,  lasting  from 
eight  to  ten  hours,  but  the  attacks  may  be  shorter  than  this  or  may  extend 
over  twenty-four  hours.  I  have  never  observed  a  quartan  infection  in  which 
the  paroxysm  lasted  over  12  hours. 

During  the  fall  in  temperature  collapse  symptoms  may  develop,  and  the 
temperature  generally  falls  considerably  below  normal,  and  may  remain 
so  during  the  apyrexial  period  and  for  some  weeks  after  recovery.  In  both 
tertian  and  quartan  malaria  the  paroxysms  are  most  apt  to  occur  during  the 
day,  usually  during  the  afternoon  or  late  morning,  but  in  both  forms  of  infection 
the  paroxysms  may  occur  during  the  night.  In  cases  of  double  or  triple  infection 
the  febrile  periods  are  apt  to  be  irregular  in  the  time  of  occurrence,  the  chill 
appearing  one  day  in  the  afternoon  and,  perhaps,  the  next  day  in  the 
morning. 

Aestivo-autumnal  Malaria. — The  aestivo-autumnal  malarial  infections 
are  caused  by  two  distinct  plasmodia,  one  completing  its  cycle  of  development  in 
the  human  body  in  24  hours  and  the  other  in  48  hours.  The  symptoms  of  the 
two  infections  differ  greatly,  especially  the  temperature,  and  in  uncomplicated 
cases  the  tertian  aestivo-autumnal  infections  may  be  diagnosed  by  the  tempera- 
ture curve  alone.  Either  of  the  aestivo-autumnal  plasmodia  is  capable  of 
causing  pernicious  symptoms,  but  personal  observations  appear  to  show  that  the 
tertian  species  is  the  one  most  commonly  concerned,  about  75  per  cent,  of  the 
pernicious  cases  I  have  observed  being  due  to  this  plasmodium. 

The  aestivo-autumnal  infections  have  long  been  distinguished  by  the  term 
"remittent  fevers,"  it  being  supposed  that  in  these  infections  the  temperature 
curve,  instead  of  presenting  the  marked  intermittency  observed  in  tertian  and 
quartan  fevers,  was  remittent  or  irregular  in  character.  This  is  not  always  so, 
however,  for  these  fevers,  when  uncomplicated  or  uninfluenced  by  quinine,  are 
as  truly  intermittent  as  are  the  tertian  and  quartan  infections.  It  is  undeniable 
that  remittency  and  irregularities  in  the  temperature  curve  are  more  common  in 
the  aestivo-autumnal  fevers,  but  too  much  stress  should  not  be  laid  upon  this 
point  in  diagnosis. 

Frequency  of  Occurrence. — The  aestivo-autumnal  infections  are  es- 
sentially tropical  malarial  infections,  and  it  is  to  these  forms  of  malaria  that  the 


THE    SYMPTOMATOLOGY    OF    THE    MALARIAL    FEVERS. 


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170  THE    SYMPTOMATOLOGY    OF    THE    MALARIAL    FEVERS. 

term  "tropical  malaria"  is  applied  by  some  writers.  As  aestivo-autumnal 
malaria  occurs  also  in  temperature  climates,  and  does  not  differ  in  its  symptoms 
from  the  same  infection  occurring  in  the  tropics,  the  term  "tropical  malaria" 
should  be  abandoned  if  by  it  we  mean  a  form  of  malaria  peculiar  to  the  tropics. 
It  is  true  that  in  the  tropics  these  infections  are  more  apt  to  become  pernicious, 
but  this  fact  is  not  due  to  any  difference  in  the  plasmodia,  but  to  the  debilitated 
condition  of  the  patient  brought  about  by  the  tropical  climate  and  by  other 
factors,  such  as  repeated  infection,  infection  with  a  great  number  of  plasmodia, 
and,  in  the  case  of  soldiers,  by  exposure  and  overexertion  beneath  a  tropical 
sun,  followed  by  the  chilling  of  the  cool  tropical  evenings. 

The  relative  frequency  of  the  occurrence  of  aestivo-autumnal  infections 
varies  very  greatly  in  different  localities.  In  the  temperate  zones  these  in- 
fections are  rare,  but  in  the  tropics  they  comprise  the  great  bulk  of  malarial 
disease,  but  even  in  the  tropics  they  are  much  more  frequent  in  some  localities 
than  in  others.  At  Camp  Stotsenburg  in  the  island  of  Luzon,  there  occurred 
from  three  to  four  cases  of  aestivo-autumnal  infection  to  one  of  tertian,  but 
at  Camp  Gregg,  only  forty  miles  from  Stotsenburg,  the  prevailing  type  of  in- 
fection was  the  benign  tertian. 

The  occurrence  of  many  cases  of  tertian  infection  in  certain  localities  in  the 
Philippine  Islands  led  to  the  report  that  aestivo-autumnal  malaria  was  in- 
frequent there,  but  a  more  careful  study  of  the  subject  has  demonstrated  that 
the  Philippines  are  not  an  exception  to  the  great  rule  that  in  the  tropics  the 
aestivo-autumnal  infections  are  the  prevailing  type.  In  2,000  cases  of  malaria 
in  soldiers  returning  from  the  Philippines  and  in  natives  of  those  islands,  in 
which  the  plasmodia  were  demonstrated  in  the  blood,  no  less  than  1,662  were 
infected  with  the  aestivo-autumnal  plasmodia.  These  personal  observations 
are  confirmed  by  those  of  Jackson,  Chamberlain,  and  others,  so  that  we  may 
state  positively  that  the  prevailing  types  of  malarial  fever  in  the  Philippine 
Islands  are  the  aestivo-autumnal. 

The  tertian  aestivo-autumnal  infections  occur  very  much  more  frequently 
than  do  the  quotidian  infections,  the  latter  type  being  comparatively  rare. 
Thus  of  1,662  aestivo-autumnal  infections,  personally  observed,  1,473  were  due 
to  the  tertian  aestivo-autumnal  plasmodium  and  only  189  to  the  quotidian 
aestivo-autumnal  plasmodium. 

The  aestivo-autumnal  infections  occur  most  frequently  in  temperate 
regions  during  the  months  of  July,  August,  September,  and  October,  but  in  the 
tropics  they  persist  throughout  the  year,  although  they  are  most  numerous 
during  the  latter  portion  of  the  rainy  season  and  at  the  beginning  of  the  dry 
season. 

In  describing  the  symptoms  of  the  aestivo-autumnal  infections  I  shall 
mention  here  only  those  observed  in  ordinary  attacks,  leaving  the  description 
of  the  symptoms  of  pernicious  attacks  for  a  succeeding  chapter.  The  symptoms 
of  this  group  of  malarial  fevers  are  very  apt  to  be  atypical  and  the  descriptions 
which  follow  apply  only  to  the  fevers  as  usually  observed. 


THE    SYMPTOMATOLOGY   OF    THE    MALARIAL    FEVERS. 


I79 


l8o  .  THE    SYMPTOMATOLOGY    OF    THE    MALARIAL    FEVERS. 

Symptoms  of  Tertian  Aestivo-autumnal  Malaria  (Non -pernicious 
Type). — Patients  suffering  from  this  type  of  malaria  will  generally  present  the 
following  symptoms: 

Prodromal. — The  prodromal  symptoms  are  loss  of  appetite,  slight  head- 
ache, evanescent  pains  in  the  back  and  legs,  nervousness,  increased  urination, 
and  a  general  feeling  of  malaise.  In  some  instances  the  onset  is  sudden,  the 
patient  having  felt  well  until  the  appearance  of  marked  symptoms.  As  in 
tertian  and  quartan  infections,  three  stages  may  be  distinguished.  The 
paroxysms  occur  every  forty-eight  hours  and  correspond  in  time  with  the 
sporulation  of  Plasmodium  falciparum. 

The  Cold  Stage  or  "Chill." — This  is  generally  initiated  by  yawning 
and  the  patient  complains  of  headache,  slight  nausea,  perhaps  accompanied  by 
vomiting,  and  often  intense  nervousness.  In  a  majority  of  the  cases  there  are 
no  distinct  chills,  but  the  patient  complains  of  chilly  "creeping"  sensations 
along  the  spinal  column  and  slight  flushings  of  cold  especially  noticeable  along 
the  posterior  aspect  of  the  buttocks  and  thighs.  At  the  same  time  the  head- 
ache increases,  there  is  present  a  feeling  of  extreme  weakness,  and  generally 
profound  mental  depression,  sometimes  so  great  as  to  be  the  most  prominent 
symptom.  The  skin  presents  the  appearance  of  "goose-flesh,"  and  it  and  the 
mucous  membranes  are  cyanosed ;  the  extremities  are  cool  and  feel  heavy  to 
the  patient.  There  is  severe  pain  and  aching  in  the  legs  and  back,  greatest, 
as  a  rule,  in  the  lumbar  region.  The  pulse  is  generally  weak  and  increased 
in  frequency  and  may  be  very  irregular.  The  respirations  are  rapid  and 
rather  shallow.  The  tongue  is  broad  and  flabby  and  heavily  coated.  During 
this  stage  the  temperature  gradually  rises  and  may  reach  1030  F.  or  more. 
This  portion  of  the  attack  does  not  last  over  half  an  hour  in  the  majority  of 
the  cases,  and  the  patient  seldom  shakes  with  the  chill  as  in  tertian  and  quar- 
tan infections. 

The  Hot  Stage. — Gradually  the  patient  experiences  a  sensation  of  heat, 
coming  first  as  localized  flushings,  but  soon  becoming  general.  The  facial  ap- 
pearance is  that  common  to  fever,  the  eyes  being  suffused  and  brilliant,  the  face 
red,  and  the  skin  dry  and  hot.  Headache  is  intense  and  there  is  present 
either  great  mental  depression  or  nervous  excitement.  The  pain  in  the  back 
and  limbs  is  often  agonizing  in  character,  and  in  some  instances  there  is  severe 
pain  over  the  abdomen,  either  over  the  spleen  or  in  the  right  iliac  region.  The 
temperature  is  elevated  and  in  uncomplicated  cases  very  characteristic.  Nausea 
and  vomiting  are  frequently  present,  the  vomiting  sometimes  being  very  severe. 
Diarrhoea  is  a  common  complication.  The  urine  is  increased  in  quantity  and 
is  generally  albuminous.  The  pulse  is  rapid  and  dicrotic  in  character,  the 
respirations  rapid,  and  there  may  be  severe  dyspnoea. 

The  Sweating  Stage  or  Stage  of  Remission. — The  hot  stage  continues 
for  several  hours  (sixteen  to  eighteen  or  twenty)  and  is  followed  by  the  falling 
of  the  temperature  accompanied  by  more  or  less  sweating.  During  the  latter 
stage  the  symptoms  gradually  decline  in  severity  and  finally  disappear,  the 


THE    SYMPTOMATOLOGY    OF    THE    MALARIAL    FEVERS. 


181 


102  THE    SYMPTOMATOLOGY    OF    THE    MALARIAL    FEVERS. 

temperature  going  a  degree  or  a  degree  and  a  half  below  normal.  A  slight 
sweating  is  generally  observed,  but  it  is  not  nearly  so  marked  as  in  tertian 
and  quartan  infections. 

The  period  of  normal  temperature  or  intermission  may  last  only  two  or 
three  hours,  when  another  paroxysm  ensues.  As  a  rule,  attacks  of  this  fever 
occur  toward  evening,  extend  throughout  the  next  day,  and  subside  during 
the  first  hours  of  the  third  day,  the  entire  paroxysm  thus  lasting  thirty-six  hours 
or  more  and  occurring  every  48  hours.  While  the  symptoms  described  are 
often  more  severe  in  this  type  of  malaria  than  they  are  in  tertian  and  quartan 
infections,  there  is  nothing  diagnostic  about  them  except  the  curve  exhibited 
by  the  temperature.  In  uncomplicated  cases  the  behavior  of  the  temperature 
is  absolutely  characteristic,  and  the  temperature  curve  is  one  that  is  not  met 
with  in  any  other  disease.  This  peculiarity  of  tertian  aestivo-autumnal 
infections  was  first  pointed  out  by  Marchiafava  and  Bignami,  and  the  writer 
has  been  able  to  confirm  their  observations  in  every  uncomplicated  case  of 
such  infection.  At  the  onset  of  the  fever  the  temperature  rises  suddenly  to 
1030  or  1040  F.  Following  the  sudden  rise  there  occur  slight  oscillations 
which  cover  several  hours,  during  which  time  the  temperature  falls  from  one- 
half  to  one  degree.  This  period  of  slight  oscillation  is  followed  by  a  distinct 
fall  or  pseudocrisis,  the  temperature  dropping  from  one  and  a  half  to  two 
or  even  three  degrees.  This  fall  in  the  temperature  is  often  considered  by 
the  physician  as  the  true  crisis  of  the  paroxysm;  on  the  contrary,  however, 
the  fever  again  rises  to  a  point  higher  than  that  before  attained  and  then  falls 
rapidly.  This  peculiar  temperature  curve  can  be  divided  into  five  stages: 
(1)  the  initial  rise;  (2)  the  period  of  slight  remissions;  (3)  the  pseudocrisis; 
(4)  the  precritical  rise;  (5)  the  true  crisis.  Another  point  of  value  in  diagnosis 
between  this  type  of  fever  and  the  benign  tertian  and  quartan  types  is  the 
length  of  the  febrile  period.  This  varies,  but  generally  the  temperature  remains 
elevated  over  24  hours,  and  often  from  38  to  40;  in  other  words,  the  paroxysm 
really  covers  two  days,  while  the  period  of  intermission  is  very  short.     (Chart  1 .) 

Symptoms  of  Quotidian  Aestivo-autumnal  Malaria. — The  quotidian 
aestivo-autumnal  fever  is  characterized  by  a  febrile  paroxysm  occurring  every 
twenty-four  hours,  corresponding  to  the  sporulation  of  Plasmodium  falciparum 
quotidianum.  Otherwise  it  varies  but  slightly  in  its  symptomatology  from 
the  tertian  type.  As  in  the  latter  form,  the  three  stages  described  may  generally 
be  observed,  but  in  the  quotidian  type  the  chilly  sensations  are  more  severe 
and  there  is  often  a  distinct  chill.  Sweating  is  also  more  pronounced,  but  is 
not  so  marked  as  in  the  simple  tertian  and  quartan  fevers.  The  temperature 
curve  is  entirely  different.  It  consists  in  the  abrupt  rise  of  the  temperature  to 
1030  F.  or  more,  succeeded  by  as  abrupt  a  fall.  The  attack  lasts,  as  a  rule,  only 
about  eight  or  ten  hours.  The  temperature  curve  seldom  remains  regular 
for  long  at  a  time,  for  the  attacks  tend  to  run  into  one  another,  thus  giving  rise 
to  more  or  less  continuous  fever.  This  is  especially  true  of  the  pernicious 
attacks.     (Chart  5.) 


THE    SYMPTOMATOLOGY    OF    THE    MALARIAL   FEVERS. 


I83 


1S4  THE    SYMPTOMATOLOGY    OF    THE    MALARIAL    FEVERS. 

To  one  who  has  studied  aestivo-autumnal  malarial  infections  in  regions 
where  they  are  endemic  and  who  has  been  so  fortuate  as  to  observe  such 
infections  uninfluenced  by  treatment  or  other  complicating  factors,  the  great 
difference  in  the  temperature  curves  of  the  tertian  and  quotidian  type  is  alone 
sufficient  to  distinguish  them,  and  when  we  add  to  this  difference  the  variation 
in  the  morphology  and  developmental  history  of  the  two  plasmodia  concerned, 
we  must  admit  that  aestivo-autumnal  malaria  is  caused  by  two  species  of  plas- 
modia, as  first  described  by  Marchiafava  and  Bignami. 

Analysis  of  the  Symptoms  of  Malarial  Infections. — It  will  be  of 
interest  and  value  to  consider  more  in  detail  the  symptoms  observed  in  the 
various  types  of  malarial  infection. 

The  Temperature  Curves  — I  have  already  spoken  of  the  temperature 
curves  exhibited  by  malarial  infections,  and,  while  in  uncomplicated  cases  a 
diagnosis  of  the  type  of  infection  might  be  arrived  at  from  a  study  of  the 
temperature  alone,  there  are  so  many  variations  from  the  typical  temperature 
in  all  forms  of  malarial  infection  that  it  is  seldom  safe  to  depend  upon  this 
symptom  in  making  a  diagnosis.  The  curves  presented  in  single  benign  tertian 
and  in  quartan  malaria  are  characteristic,  the  febrile  paroxysm  in  the  one  occur- 
ring at  the  end  of  every  48  hours,  in  the  other  at  the  end  of  every  72  hours, 
but  in  double  or  triple  infections  or  in  mixed  infections,  the  temperature  curve 
may  be  so  altered  as  to  be  of  no  service  in  diagnosis.  In  the  tertian  aestivo- 
autumnal  cases  the  temperature  curve  is  very  characteristic  in  uncomplicated 
cases,  but  many  cases  occur  in  which  the  curve  is  so  altered  as  to  be  unrecogniza- 
ble. In  a  large  proportion  of  tertian  aestivo-autumnal  cases,  the  characteristic 
temperature  curve  already  described  will  be  observed,  but  there  are  many 
deviations  from  the  classical  type.  These  deviations,  in  all  forms  of  malaria, 
are  due  to  several  factors,  among  the  most  important  of  which  are  the  following: 
improper  medication  with  quinine;  double  infections  or  infections  with  more 
than  one  species  of  the  malarial  plasmodium;  anticipation  of  the  attacks, 
especially  common  in  the  pernicious  fevers;  retardation  of  the  attacks;  slight 
elevations  of  temperature  between  the  attacks,  and  complication  with  some 
other  disease. 

The  most  beautifully  typical  malarial  temperature  curve  may  be  rendered 
atypical  and  very  confusing  by  the  administration  of  small  doses  of  quinine 
at  irregular  intervals,  and  this  is  one  of  the  most  common  causes  of  irregularity 
in  the  curve. 

The  most  important  alterations  in  the  tertian  aestivo-autumnal  tempera- 
ture curve  produced  by  the  factors  enumerated  are: 

1.  A  curve  almost  identical  with  that  of  the  benign  tertian,  produced  by 
the  short  duration  of  the  paroxysm.     (Chart  No.  2.) 

2.  A  curve  characterized  by  a  long  period  of  slight  remissions,  due  to 
prolongation  of  the  paroxysms.     (Chart  No.  3.) 

3.  A  curve  showing  no  well-marked  initial  elevation  of  the  temperature, 
thus  causing  a  more  or  less  continuous  fever  line. 


THE    SYMPTOMATOLOGY    OF    THE    MALARIAL    FEVERS. 


J8; 


H 


l86  THE    SYMPTOMATOLOGY    OF    THE    MALARIAL    FEVERS. 

4.  A  continuous  curve  showing  only  slight  remissions,  due  to  overlapping 
of  the  paroxysms.     (Chart  No.  4.) 

5.  A  curve  showing  a  very  marked  pseudocrisis,  thus  causing  the  fever 
line  to  resemble  that  of  a  double  tertian  or  quotidian  aestivo-autumnal 
infection. 

6.  A  curve  in  which  the  five  stages  described  are  reversed. 

Besides  these'  modifications  there  occur  many  which  are  so  complex  that 
it  becomes  impossible  to  recognize  the  disease  with  which  we  are  dealing  with- 
out a  microscopical  examination  of  the  blood. 

In  the  aestivo-autumnal  fevers  a  temperature  chart  which  shows  only  the 
morning  and  evening  temperature  is  worse  than  useless  as  a  guide  in  study  or 
diagnosis,  and  the  use  of  a  chart  showing  the  temperature  every  three  or  four 
hours  is  imperative.  To  secure  the  most  typical  temperature  curve  the  chart 
should  be  a  three-hourly  one,  and  only  by  the  use  of  such  a  chart  can  the  peculiar 
curve  of  tertian  aestivo-autumnal  malaria  be  demonstrated. 

In  the  quotidian  form  of  aestivo-autumnal  malaria  the  temperature  curve 
is  not  very  characteristic.  The  temperature  rises  quickly  and  falls  as  quickly, 
the  entire  attack  lasting,  as  a  rule,  about  eight  hours,  but  sometimes  longer, 
while  in  the  typical  form  the  temperature,  during  the  crisis,  falls  considerably 
below  normal.  This  is  a  very  marked  peculiarity  of  the  quotidian  form,  and  in 
no  other  disease  does  the  temperature  fall  so  far  below  normal  without  a  fatal 
result  to  the  patient.  I  have  seen  many  cases  in  which  the  temperature  fell  to 
950  F.  during  the  crisis,  and  several  in  which  it  fell  even  lower,  without  any 
symptoms  of  collapse  developing.  As  the  curve  in  this  form  of  aestivo- 
autumnal  infection  resembles  so  closely  that  of  a  double  tertian  infection,  we 
are  forced  to  depend  upon  the  microscope  in  order  to  exclude  the  latter,  and 
there  is  no  greater  proof  of  the  value  of  a  microscopical  examination  of  the  blood 
than  is  found  in  the  ease  with  which  the  various  forms  of  malarial  fever  may 
be  diagnosed  and  differentiated  by  it,  and  such  an  examination  is  often  instru- 
mental in  saving  life. 

The  Chills.— In  benign  tertian  and  in  quartan  infection  the  chills  are 
pronounced  in  the  vast  majority  of  instances,  although  very  rarely  such  in- 
fections are  observed  in  which  the  patients  complain  only  of  chilly  sensations. 
In  the  aestivo-autumnal  infections,  however,  the  chill  is  slight  or  almost  absent, 
especially  in  the  tertian  form.  In  the  majority  of  cases  the  patients  simply  com- 
plain of  chilly  sensations  along  the  spinal  column  and  seldom  shake  with  the 
chill.  In  the  quotidian  infections  the  chill  is  more  pronounced  than  in  the  ter- 
tian form,  and  in  both  occur  cases  in  which  the  chill  may  be  very  severe  and 
exhausting.  There  are  also  many  cases  in  which  the  chill  is  so  slight  as  not  to 
attract  the  attention  of  the  patient.  As  a  rule,  the  chilly  sensations  or  the  chill 
do  not  last  over  three-quarters  of  an  hour,  and  in  the  aestivo-autumnal  in- 
fections often  not  over  fifteen  to  twenty  minutes.  In  general,  it  may  be  said 
that  shaking  chills  occur  commonly  in  simple  tertian  and  quartan  malaria,  very 
rarely  in  aestivo-autumnal  infections. 


THE    SYMPTOMATOLOGY    OF    THE    MALARIAL    FEVERS. 


I87 


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188  THE    SYMPTOMATOLOGY    OF    THE    MALARIAL    FEVERS. 

The  Sweating. — In  simple  tertian  and  quartan  infections  the  sweating 
which  occurs  during  the  decline  of  the  febrile  paroxysm  is  generally  profuse  and 
sometimes  very  exhausting.  In  these  cases  the  entire  skin  is  covered  with  per- 
spiration, often  so  great  in  quantity  that  the  water  may  be  seen  trickling  down 
the  trunk  and  limbs,  saturating  the  bed-clothing.  In  the  tertian  aestivo-autumnal 
infection  the  sweating  is  not  excessive,  and  is  often  so  slight  as  not  to  at- 
tract attention.  In  the  quotidian  form  the  sweating  is  generally  more  severe, 
but  not,  as  a  rule,  so  marked  as  in  the  simple  tertian  or  quartan  infections.  In 
both  forms  of  aestivo-autumnal  fever,  however,  the  sweating  stage  may  be 
prolonged  and  exhausting. 

Facial  Appearance. — In  primary  acute  attacks  of  all  forms  of  malaria  the 
face  is  flushed  or  congested,  the  eyes  suffused  and  brilliant,  while  an  anxious  ex- 
pression is  often  present  and  the  patient  looks  very  sick.  Exceptions  to  this 
rule  are  observed  in  which  the  face  is  pale  and  the  patient  appears  indifferent  or 
even  cheerful.  In  cases  which  have  suffered  from  relapses  the  face  is  usually 
brownish-yellow  in  color,  slightly  flushed  and  haggard  looking. 

The  Skin. — In  primary  acute  attacks  of  malaria  there  is  no  alteration  in 
the  color  of  the  skin,  but  in  the  majority  of  patients  who  have  suffered  from 
relapses,  especially  of  the  aestivo-autumnal  fevers,  the  skin  assumes  a  grayish 
or  yellowish  hue  and  appears  very  anaemic.  In  some  aestivo-autumnal  in- 
fections, notably  the  so  called  "bilious  remittent  fever,"  the  skin  may  be  mark- 
edly jaundiced,  so  much  so  as  to  suggest  yellow  fever. 

During  acute  attacks  of  all  of  the  malarial  fevers  various  skin  eruptions  may 
make  their  appearance,  especially  urticarial  eruptions,  which  I  have  observed 
often  in  aestivo-autumnal  fever.  Herpes  of  the  lips  is  a  very  common  symptom 
in  some  localities  and  in  some  infections,  but  is  not  as  common  in  all  localities  as 
has  been  supposed.  Thus  F.  Plehn,  in  Africa,  observed  herpes  only  once  in  714 
cases  of  malaria,  and  my  own  experience  in  the  Philippines  is  corrobative  of  that 
of  this  observer.  Of  over  500  cases  of  malaria  observed  in  Luzon,  P.  I.,  I  saw 
only  about  10  cases  in  which  herpes  occurred,  while  at  San  Francisco  and  in 
Cuba  this  condition  was  much  more  common,  although  all  of  the  cases  observed 
at  San  Francisco  were  in  the  person  of  soldiers  returning  from  the  Philippines 
and  who  had  contracted  their  malaria  in  those  islands.  It  would  thus  appear 
that  locality  has  much  to  do  with  the  frequency  of  the  occurrence  of  this  symp- 
tom. Herpes  of  the  nostrils  is  not  uncommon,  and  in  several  cases  of  aestivo- 
autumnal  malarial  I  have  observed  herpes  of  the  penis  occurring  with  or 
immediately  after  a  paroxysm  of  fever. 

Peeling  of  the  skin  is  sometimes  observed  in  aestivo-autumnal  infections, 
occurring  during  an  acute  attack.  I  remember  such  a  case  in  which  the  peeling 
was  very  extensive,  portions  of  the  epidermis  several  centimeters  in  diameter 
being  thrown  off. 

The  Mouth  and  Tongue. — The  mouth,  during  the  paroxysms,  is  dry, 
the  tongue  thickly  coated  with  a  dirty  white  or  brownish  fur,  and  either  broad 
and  flat  or  pointed  and  narrow.     In  severe  cases  of  aestivo-autumnal  fever  the 


THE    SYMPTOMATOLOGY   OF    THE    MALARIAL    FEVERS.  189 

tongue  is  dry  and  coated  with  a  thick  brown  fur,  while   in  pernicious  cases 
sordes  may  form  upon  the  lips  and  teeth  as  in  typhoid  fever. 

Symptoms  Connected  with  the  Circulatory  System. — The  organs  of 
circulation  are  generally  but  slightly  affected  during  a  malarial  paroxysm. 
The  heart  sounds  are  usually  clear,  but  often  a  slight  systolic  murmur  may  be 
heard  over  the  mitral  region.  In  many  instances,  however,  the  heart  sounds 
are  muffled  or  the  second  sound  is  increased  in  volume.  During  the  chill, 
especially  if  it  be  severe,  (and,  therefore,  more  commonly  in  the  simple  tertian  and 
quartan  infections  than  in  the  aestivo-autumnal),  the  pulse  is  weak  and  rapid; 
during  the  stage  of  fever  it  is  full,  easily  compressible,  and  often  remarkably 
dicrotic.  It  is  increased  in  frequency,  averaging  from  120  to  140  beats  per 
minute.  During  the  decline  of  the  fever  the  pulse  is  full  in  volume  and  dicrotic, 
while  it  is  decreased  in  frequency.  Sometimes  there  is  present  a  marked 
bradycardia.  In  not  a  few  cases  of  aestivo-autumnal  infection  the  pulse  will  be 
found  intermittent  and  sometimes  alarmingly  irregular,  and  I  have  observed 
instances  in  which  the  first  symptom  of  the  malarial  paroxysm  consisted  in 
temporary  failure  of  the  heart's  action.  In  many  cases  the  patient  complains  of 
a  dull  or  acute  precardial  pain.  The  area  of  heart  dullness  is  not  altered  in 
uncomplicated  cases. 

Symptoms  Connected  with  the  Respiratory  System.- — -The  respirations 
are  always  increased  in  frequency  during  an  acute  attack  of  any  of  the  malarial 
fevers,  and  in  severe  cases  often  appear  to  be  slightly  labored.  This  condition 
is  due  to  the  greater  or  lesser  amount  of  congestion  present  in  the  lungs  and  the 
high  temperature.  Dyspnoea  is  present  in  some  of  the  more  severe  infections, 
and  acute  bronchitis,  of  mild  character,  is  a  very  common  symptom  during  acute 
attacks  of  aestivo-autumnal  fever.  In  rare  instances  symptoms  indistinguishable 
from  those  of  pneumonia  may  appear,  accompanied  by  a  limited  amount  of 
blood-stained  sputum. 

Physical  examination  of  the  lungs  may  show  slight  areas  of  lessened 
resonance  and  a  few  rales,  chiefly  sibilant  in  character.  Moist  rales  are  some- 
times heard.     The  physical  signs  of  an  acute  bronchitis  are  often  demonstrable. 

Symptoms  Connected  with  the  Digestive  System. — In  all  cases  of 
malaria  there  is  loss  of  the  appetite,  often  observable  for  days  before  the  onset 
of  the  febrile  paroxysm.  A  feeling  of  oppression  in  the  stomach  or  actual  pain 
in  that  region  are  common  symptoms  during  the  paroxysm  and  sometimes 
for  days  afterward.  Nausea  is  a  very  common  symptom  in  all  forms  of 
malarial  infection,  whether  acute  or  chronic,  occurring  in  fully  90  per  cent,  of 
all  cases,  and  this  symptom  is  often  very  distressing  and  exhausting.  Vomiting 
occurs  in  a  large  proportion  of  all  cases  and  in  some  instances  is  so  severe  and 
persistent  as  to  endanger  the  patient's  life.  Diarrhoea  is  another  common 
symptom,  occurring  during  the  paroxysm  or  immediately  afterward,  and  rarely 
may  be  of  serious  import.  Constipation  is  more  commonly  observed,  however, 
and  may  be  present  for  days  before  the  onset  of  the  fever. 

Pain  over  the  stomach  and  abdomen  is  not  infrequently  met  with  and  has 


I90  THE    SYMPTOMATOLOGY    OF    THE    MALARLA.L    FEVERS. 

been  the  cause  of  many  mistaken  diagnoses.  I  have  repeatedly  seen  cases 
of  malaria  with  severe  pain  in  the  region  of  the  appendix  diagnosed  as  appendi- 
citis, and  in  more  than  one  instance  the  microscope  saved  the  patient  an 
operation.  In  some  cases  there  is  general  pain  over  the  abdomen  simulating 
very  closely  that  of  a  general  peritonitis.  I  have  observed  instances  in  which 
the  abdominal  pain  was  agonizing  in  character,  and  controlled  only  by  large 
doses  of  morphine. 

Symptoms  Connected  with  the  Glandular  System. — Enlargement 
of  the  spleen  during  an  acute  initial  attack  of  malaria  is  by  no  means  constant. 
While  there  can  be  no  doubt  but  that  the  organ  is  enlarged  slightly  in  all  acute 
infections,  the  enlargement  in  many  cases  is  not  demonstrable,  and  a  very  large 
proportion  of  the  cases  do  not  present  a  palpable  spleen.  In  cases,  however, 
which  have  suffered  from  malarial  infection  for  a  considerable  period  of  time, 
and  in  which  there  have  been  many  relapses,  the  splenic  enlargement  is  gener- 
ally noticeable,  the  organ  being  plainly  palpable,  and  often  extending  nearly  to 
the  umbilicus  or  perhaps  beyond  it.  Laveran  claims  that  every  case  of  malaria 
shows  an  enlargement  of  the  spleen,  while  Kelsch  and  Kiener,  A.  Plehn,  and 
others  state  that  this  organ  is  often  not  enlarged.  It  is  probable  that  much  of 
the  confusion  regarding  this  matter  is  due  to  lack  of  accuracy  in  making  the 
physical  examination  and  in  clearly  defining  the  method  of  examination.  Thus 
in  many  cases  careful  percussion  will  show  enlargement  of  the  organ,  although 
it  may  not  be  palpable.  From  my  own  experience  I  have  learned  that  palpable 
enlargement  is  much  less  common  than  has  hitherto  been  supposed,  but  that 
in  almost  every  case  the  organ  will  be  found  enlarged  upon  percussion.  Manna- 
berg  claims  that  in  88  per  cent,  of  cases  suffering  from  malaria,  the  spleen  is 
palpable,  while  in  the  remaining  12  per  cent,  it  is  enlarged  to  percussion. 

The  spleen  is  palpable  in  aestivo-autumnal  malaria  more  frequently 
than  in  simple  tertian  or  quartan  infections,  because  the  aestivo-autumnal 
infections  are  more  resistant  to  treatment  and  more  prone  to  relapse.  In 
recent  infections  the  organ  is  soft  and  rounded  and  very  tender  upon  pressure, 
while  in  old  infections  it  is  hard  and  presents  a  well-defined,  rather  sharp 
margin. 

In  acute  infections  the  liver  is  often  slightly  enlarged  and  tender,  especially 
in  cases  which  have  suffered  from  numerous  relapses. 

Symptoms  Connected  with  the  Urinary  System. — In  many  cases  of 
malaria  polyuria  is  a  prominent  symptom,  occurring  before,  during,  or  after  a 
paroxysm.  Pain  in  the  lumbar  region,  over  the  kidneys,  is  a  very  common 
symptom,  and  direct  pressure  upon  these  organs  is  sometimes  exquisitely 
painful.  In  a  large  proportion  of  the  cases,  however,  the  lumbar  pain  is  not 
referable  to  the  kidneys. 

Symptoms  Connected  with  the  Nervous  System. — While  symptoms 
referable  to  the  nervous  system  occur  in  all  forms  of  malaria,  it  is  in  the  aestivo- 
autumnal  fevers  that  they  are  most  frequent  and  most  important.  The 
malarial  toxin  appears  to  have  a  marked  affinity  for  the  tissues  of  the  nervous 


THE    SYMPTOMATOLOGY    OF    THE    MALARIAL    FEVERS.  I9I 

system  and  its  action  upon  the  vasomotor  centers  is  well  illustrated  in  the 
phenomena  of  the  malarial  paroxysm,  i.e.,  chill,  fever  and  sweating.  Delirium 
occurs  in  a  fairly  large  percentage  of  cases  of  aestivo-autumnal  malaria,  and 
in  severe  tertian  and  quartan  cases,  and  is  usually  of  a  mild,  quiet  type;  active 
maniacal  delirium  is  sometimes  observed.  Headache  occurs  in  practically 
every  case  and  is  very  often  severe  and  most  distressing.  It  is  usually  referred 
to  the  forehead  and  occiput,  and  persists  throughout  the  paroxysm,  and  often  in 
the  afebrile  interval.  Soreness  of  the  scalp  is  often  complained  of  after  the 
paroxysm.  Stupor  is  a  common  accompaniment  of  the  more  severe  forms  of 
all  the  malarial  fevers,  and  coma  is  common  in  pernicious  cases.  Vertigo 
and  tinnitus  aurium  are  common  and  annoying  symptoms.  Patients  suffering 
from  the  aestivo-autumnal  infections  are  often  extremely  nervous,  both  during 
and  between  the  paroxysms,  and  not  infrequently  this  condition  deepens  into 
a  mild  form  of  melancholia;  such  cases  should  be  carefully  watched,  as  suicidal 
tendencies  are  apt  to  develop. 

Pain  in  the  back  and  limbs  is  always  present  during  acute  attacks  of  malaria, 
and  may  be  very  severe,  and  is  always  one  of  the  most  disagreeable  things  the 
patient  is  called  upon  to  bear. 

The  more  severe  nervous  symptoms  occasionally  observed  in  severe 
malarial  attacks,  such  as  aphasia,  paraplegia,  hemiphegia,  epileptiform 
convulsions,  and  mania  will  be  considered  in  the  chapter  dealing  with  the 
complications  of  malaria. 

Examination  of  the  Blood. — I  have  already  noted  and  described  the 
blood  changes  occurring  during  malarial  infection,  and  will  consider  here  the 
blood  findings  as  regards  the  plasmodia  during  the  clinical  periods  of  the 
fevers. 

Simple  Tertian  Malaria. — During  the  febrile  paroxysm  an  examination 
of  the  blood  will  show  the  presence  of:  1.  Sporulating  plasmodia.  2.  Fully 
developed  pigmented  intracellular  plasmodia.  3.  Young  hyaline  ring-forms. 
Examined  at  various  hours  during  the  afebrile  period,  the  plasmodia  may 
be  followed  in  development  from  the  unpigmented  and  slightly  pigmented 
organism,  filling  only  a  portion  of  the  infected  cell,  to  the  fully  grown  plasmodium, 
containing  much  pigment  and  filling  and  distending  the  infected  red  corpuscle. 
An  hour  or  two  before  the  onset  of  the  paroxysm,  the  blood  contains  only 
fully  developed  forms  and  sporulating  bodies. 

In  double  infections  all  stages  of  the  plasmodium  can  be  found  at  the  same 
time. 

Quartan  Malaria. — An  examination  of  the  blood  in  quartan  malaria 
gives  the  same  results  as  in  simple  tertian  as  regards  the  stage  of  development  of 
the  plasmodium. 

Tertian  Aestivo-autumnal  Malaria. — During  the  febrile  period,  an 
examination  of  the  peripheral  blood  shows  the  small,  more  or  less  amoeboid, 
hyaline,  intracorpuscular  plasmodia,  from  one-tenth  to  one-sixth  the  size  of  the 
red  corpuscle. 


I92  THE    SYMPTOMATOLOGY    OF    THE    MALARIAL    FEVERS. 

During  the  afebrile  stage  the  young  pigmented  forms  are  found  in  the 
peripheral  blood. 

Before  the  onset  of  a  paroxysm  the  pigmented  forms  are  more  numerous 
and  have  attained  their  largest  size,  about  one-fourth  that  of  the  infected  red 
cell. 

At  the  commencement  of  a  paroxysm  the  plasmodia  are  generally  remark- 
ably few  in  number  in  the  peripheral  blood,  but  the  young  unpigmented  forms 
appear  about  at  the  acme  of  the  fever. 

In  this  form  of  malarial  infection  it  is  but  very  rarely  that  sporulating  forms 
are  found  in  the  peripheral  blood,  but  blood  secured  by  puncture  of  the  spleen 
at  the  time  of  the  paroxysm  will  show  multitudes  of  these  bodies. 

Quotidlvn  Aestivo-autumnal  Malaria. — The  examination  of  the  blood 
in  cases  of  quotidian  aestivo-autumnal  malaria  gives  results  substantially  the 
same  as  those  obtained  in  the  tertian  type  as  given  above,  so  far  as  the  time  of 
appearance  of  the  plasmodia  in  the  peripheral  blood  is  concerned,  so  that  it  is 
unnecessary  to  describe  them  separately. 

In  mixed  infections  and  in  irregular  aestivo-autumnal  infections  the 
examination  of  the  blood  will  show  the  presence  of  the  plasmodia  concerned, 
but  it  is  difficult  in  such  cases  to  trace  the  cycle  of  development  of  the  parasites 
of  any  one  group. 

Malaria  in  Children. — Because  malarial  infections  in  children  present 
important  differences  in  their  symptomatology  from  the  same  infections  occur- 
ring in  adwlts,  it  is  necessary  that  we  should  speak  of  such  infections  somewhat 
in  extenso. 

Frequency. — It  has  already  been  mentioned  that  in  malarial  localities  the 
children  suffer  much  more  severely  than  do  the  adults,  and  that  malaria  tends  to 
disappear  with  increasing  years.  It  is  not  necessary  here  to  recapitulate  the 
evidence  collected  upon  this  point  which  has  been  given  in  a  preceding  chapter 
but  the  important  point  should  be  remembered  that  in  children  malaria  is  very 
often  latent  and  that  in  malarial  localities  the  children  furnish  almost  all  of  the 
pernicious  cases.  The  infantile  mortality  from  malaria  in  the  tropics  is  enor- 
mous and  very  largely  preventable. 

The  symptoms  of  malarial  infection  in  young  children  are  so  slight  in  many 
instances  that  for  days  and  even  weeks  such  an  infection  may  be  present  without 
attracting  attention.  In  the  Philippines  I  have  often  seen  children  playing  about 
the  streets  with  a  temperature  of  ioo°  to  1010  F.  and  their  blood  swarming 
with  plasmodia.  In  young  children  the  onset  of  a  malarial  paroxysm  is  often 
marked  by  convulsions  and  the  nervous  symptoms  are  pronounced  throughout 
the  attack.  In  other  cases  the  onset  is  preceded  by  yawning  and  drowsiness, 
or  by  severe  headache.  The  chill  is  frequently  absent  or  very  slight,  but  the 
hot  stage  is  marked,  the  temperature  prolonged,  and  the  sweating  very  slight 
or  entirely  absent.  In  many  cases  the  only  symptom  of  importance  is  the  fever 
which  may  be  almost  continuous  or  very  irregular,  lasting  from  a  few  hours  to 
several  days.     Spontaneous  recovery  is  common  and  relapses  are  frequent. 


THE    SYMPTOMATOLOGY    OF    THE    MALARIAL    FEVERS.  i  93 

Enlargement  of  the  spleen  is  not  apparent  in  more  than  half  of  the  1  a  e  , 
Pain  in  the  stomach  is  a  common  symptom  in  children  and  vomiting  and  diar- 
rhoea occur  very  frequently.  In  certain  cases  a  fatal  diarrhoea  may  occur,  and 
convulsions  and  coma  are  common  in  pernicious  cases.  In  children  over  three 
years  of  age  the  symptoms  are  more  like  those  occurring  in  the  adult,  and  the 
diagnosis  is  more  easily  made  in  older  children. 

It  is  obvious  that,  in  malarial  localities  especially,  the  diagnosis  of  these 
infections  in  children  is  of  the  very  greatest  importance  from  both  a  prophylactic 
and  therapeutic  standpoint.  The  atypical  character  of  the  symptoms  renders  a 
clinical  diagnosis  difficult,  and  in  many  instances  impossible,  and  we  have  to 
depend  upon  the  microscope  in  arriving  at  a  diagnosis.  In  every  malarial 
locality  the  blood  of  all  the  children  should  be  examined  and  this  procedure 
should  be  as  much  a  part  of  the  sanitary  police  of  a  locality  as  the  proper  dis- 
posal of  sewage  or  the  care  of  the  water  supply,  for  it  will  thus  be  possible  to 
distinguish  those  infected  with  malaria  and  to  institute  proper  measures  for 
prevention  and  cure  of  the  disease.  It  is  not  too  much  to  expect  that  the  en- 
forcement of  such  a  measure  in  badly  infected  localities  will  in  time  render 
them  practically  free  from  malaria. 


13 


CHAPTER   II. 

Clinical  Illustrations  of  the  Tertian  and  Quotidian  Aestivo-autumnal 
Malarial  Fevers. 

Because  of  their  interest  and  importance  I  have  selected  for  description 
in  this  chapter  a  number  of  typical  cases  of  tertian  and  quotidian  aestivo-autum- 
nal fever  observed  in  soldiers  returning  from  Cuba  in  1898  and  1899.  I  have 
selected  these  cases  from  hundreds  of  others  because  they  were  studied  for 
several  days  before  quinine  was  administered,  and  thus  all  of  the  typical 
phenomena  of  the  paroxysm  were  observed.  From  the  charts  shown  it  will  be 
observed  that  these  cases  conformed  to  one  of  two  types  of  fever,  tertian  or 
quotidian,  and  the  examination  of  the  blood  demonstrated  that  they  were  due  to 
two  distinct  plasmodia,  which  could  be  differentiated  morphologically.  I 
believe  that  the  following  cases  prove  conclusively  that  two  varieties  of  aestivo- 
autumnal  fever  occur,  each  characterized  by  its  own  peculiar  clinical  course 
and  by  the  presence  in  the  blood  of  a  specific  plasmodium. 

In  considering  these  cases  I  have  aimed  to  give  only  the  salient  features, 
both  clinical  and  microscopical  in  each  instance,  and  it  should  be  remembered 
that  there  are  many  exceptions  to  the  typical  types  as  illustrated  in  this  chapter. 
Cases  occur  in  which  the  temperature  curve  is  more  or  less  continuous,  and  in 
which  there  are  found  multiple  groups  of  parasites  or  combined  infections  with 
more  than  one  species  of  malarial  plasmodium.  In  such  cases  the  symptoms  are 
often  atypical,  and  the  temperature  curves  are  most  irregular  and  confusing. 
It  matters  not  how  typical  the  temperature  curve  may  be,  however,  in  a  case  of 
aestivo-autumnal  fever,  it  can  be  easily  made  atypical  by  the  administration  of 
insufficient  doses  of  quinine  given  at  irregular  intervals.  Such  treatment,  far 
too  common,  will  cause  the  most  typical  temperature  curve,  whether  tertian  or 
quotidian,  to  become  irregular  and  often  altogether  unrecognizable  as  one  of 
malaria,  and  is  the  most  prolific  source  of  the  existing  confusion  regarding  the 
classification  of  the  aestivo-autumnal  fevers.  In  combined  infections  with 
both  the  tertian  and  quotidian  plasmodium,  a  more  or  less  continued  or  slightly 
remittent  temperature  curve  is  seen,  while  in  cases  in  which  quinine  in  un- 
suitable doses  has  been  given,  an  irregular,  intermittent  temperature  curve  is 
most  common.  Where,  however,  no  combination  of  the  two  species  of  plasmo- 
dium exists  and  quinine  has  not  been  administered,  it  will  almost  invariably  be 
found  that  either  a  tertian  or  quotidian  temperature  curve  will  be  observed  in 
aestivo-autumnal  infections  in  which  only  one  group  of  plasmodia  is  under- 
going development. 

194 


THE   AESTIVO-AUTUMNAL    MALARIAL    FEVERS.  1 95 

Cases  of  Quotidian  Aestivo-autumnal  Malaria. 

There  is  nothing  peculiar  about  the  temperature  curve  in  this  form  of 
malarial  fever,  it  very  closely  resembling  an  ordinary  double  tertian  curve.  It 
is  a  notable  fact,  however,  that  many  cases  of  pernicious  malarial  fever  present 
this  type  of  temperature  curve,  and  the  blood  has  shown  the  characteristic 
quotidian  aestivo-autumnal  plasmodium.  None  of  the  cases  described  in  this 
chapter  were  pernicious  in  character,  as  I  have  purposely  selected  those  of  a 
milder  type,  because  they  are  so  much  more  common. 

Case  I.  Chart  6. — Hamilton.  The  patient,  a  soldier,  arrived  at  Santiago, 
Cuba,  in  August,  1898.  He  was  there  about  one  month  when  he  developed 
measles,  which  was  followed  by  dysentery.  About  the  middle  of  October  he 
began  to  have  chills  and  fever.  His  chills  occurred,  as  a  rule,  every  day,  but 
were  sometimes  irregular.  Besides  the  chills  he  suffered  from  nausea,  vomiting, 
severe  headache,  and  diarrhoea.  Has  had  several  attacks  followed  by  recovery 
under  treatment.  He  was  feeling  well  on  his  arrival  at  the  hospital,  June  23, 
1899.  Upon  the  26th  he  began  to  run  a  temperature  characterized  by  quotidian 
paroxysms,  but  had  no  distinct  chill  until  the  30th.  Up  to  the  latter  date  he 
suffered  from  nausea,  some  headache,  and  general  pains.  On  the  30th  he  had  a 
distinct  chill,  suffered  from  nausea,  vomiting,  sweating,  severe  frontal  headache, 
and  general  pain,  especially  severe  between  the  shoulders.  His  bowels  were 
constipated. 

Physical  Examination. — Patient  is  anaemic  and  emaciated.  Skin 
slightly  yellow;  face  flushed;  tongue  heavily  coated  with  a  thick,  yellowish  fur, 
and  flabby;  lungs  and  heart  normal;  pulse  full  and  bounding;  spleen  enlarged 
and  tender,  reaching  about  4  cm.  below  ribs;  liver  normal.  Some  tenderness 
over  abdomen  on  deep  pressure,  probably  due  to  pressure  on  spleen. 

Examination  or  the  Blood. — The  blood  was  examined  daily  at  intervals 
until  the  parasites  disappeared.  It  was  found  that  they  were  most  numerous 
in  the  peripheral  blood  during  or  just  after  a  paroxysm,  but  at  no  time  were 
they  numerous  enough  to  show  more  than  one  infected  corpuscle,  on  the  average, 
to  the  field.  The  parasites  were  typical  of  the  quotidian  aestivo-autumnal 
variety,  and  two  forms  were  observed  in  the  peripheral  blood:  the  "ring"  forms 
and  the  pigmented  bodies.  The  ring  forms  were  very  small,  indistinct  in  out- 
line, perfectly  circular  when  at  rest,  and  very  actively  amoeboid.  They  never 
showed  the  "signet  ring"  appearance  so  common  in  the  tertian  variety,  and 
were  never  more  than  one-sixth  the  size  of  the  infected  red  corpuscle.  Some 
infected  corpuscles  contained  two,  and  a  few  even  three  plasmodia.  The 
pigmented  forms  were  about  one-fourth  the  size  of  the  infected  cell,  which  was 
always  shrunken,  brassy  green  in  color,  and  generally  crenated.  The  outline 
of  the  pigmented  forms  was  sharply  defined,  and  they  were  perfectly  circular  in 
shape,  amoeboid  motion  being  absent.  The  pigment  occurred  in  the  form  of 
one  or,  at  most,  two  rather  large,  almost  black  dots,  either  centrally  or  per- 
ipherally situated.     The  pigment  was  almost  motionless.     No  segmenting  forms 


196 


THE   AESTIVO-AUTUMNAL    MALARIAL   FEVERS. 


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THE   AESTIVO-AUTUMNAL    MALARIAL    FEVERS.  1 97 

or  crescents  (gametes)  were  observed  in  this  case.  The  plasmodia  disappeared 
from  the  peripheral  blood  two  days  after  the  commencement  of  the  administra- 
tion of  quinine. 

Treatment. — Quinine,  in  doses  of  grm.  0.325,  every  four  hours. 

Upon  reference  to  the  temperature  chart  it  will  be  seen  that  there  is  nothing 
very  distinctive  about  the  temperature  curve,  beyond  its  quotidian  character, 
and -the  fact  that  during  the  first  three  paroxysms  the  patient  had  no  chills, 
suffering  only  from  chilly  sensations,  while  during  the  fourth  paroxysm  even 
the  chilly  sensations  were  absent.  The  first  distinct  chill  occurred  during  the 
fifth  paroxysm.  The  temperature  curve  might  well  be  taken  for  that  of  a 
double  tertian  infection,  the  microscope  alone  being  serviceable  in  differen- 
tiating the  type  of  infection  present.  The  temperature  reached  normal  after 
two  days'  treatment.  The  subnormal  temperature  of  95. 40  F.  upon  the  29th 
is  worthy  of  notice,  as  it  has  been  my  experience  that  in  no  disease  does  the 
temperature  so  often  reach  low  sub-normal  points  as  in  this  form  of  aestivo- 
autumnal  fever. 

Case  II.  Chart  7. — S.  F.  S.  The  patient,  a  soldier,  suffered  for  several 
weeks  in  Santiago,  Cuba,  from  attacks  of  fever,  accompanied  by  chilly  sensa- 
tions, headache,  backache,  slight  nausea,  and  sweating.  He  grew  gradually 
weaker  and  was  transferred  to  the  United  States,  arriving  at  the  hospital  on 
January  23,  1899.  His  temperature  remained  normal  until  the  twenty-sixth, 
when  he  had  a  chill,  which  was  repeated  every  day  for  four  days.  During 
this  time  he  suffered  from  severe  headache,  with  much  mental  depression, 
backache,  darting  pains  down  the  legs,  and  nausea. 

Physical  Examination. — Much  emaciated;  skin  of  a  peculiar  grayish- 
yellow  hue;  tongue  thickly  coated  and  flabby;  expression  listless  and  depressed; 
heart  and  lungs  normal;  pulse  rapid,  full  and  strong;  spleen  enlarged  and 
tender,  reaching  about  6  cm.  below  the  border  of  the  ribs;  liver  slightly  en- 
larged; bowels  constipated. 

Examination  or  the  Blood. — The  blood  was  examined  daily  at  regular 
intervals  and  showed  very  numerous  quotidian  aestivo-autumnal  plasmodia. 
Ring-forms  and  pigmented  forms  were  common,  and  upon  one  occasion  two 
segmenting  forms  were  observed  in  the  peripheral  blood.  The  organisms 
appeared  to  be  most  numerous  during  the  latter  portion  of  the  paroxysm. 
The  ring-forms  were  very  minute,  indistinct  in  outline,  and  actively  amoeboid. 
The  pigmented  forms  were  circular  or  oval  in  shape,  and  contained  one  or  two 
nearly  black  pigment  dots.  The  segmenting  forms  were  intracorpuscular  and 
in  one  instance  the  segments  numbered  six,  in  the  other  eight.  Numerous 
corpuscles  showed  double  or  triple  infection. 

Treatment. — Quinine  grm.  0.65  every  four  hours. 

The  temperature  chart  in  this  case  shows  an  unusually  high  range  of  fever 
for  a  quotidian  aestivo-autumnal  infection,  but  is  not  otherwise  remarkable. 
It  resembles,  even  more  closely  than  that  of  Case  I,  an  ordinary  double  tertian 
chart,  and  it  would  obviously  be  impossible  to  make  a  diagnosis  of  the  type  of 


198 


THE   AESTIVO-AUTUMXAL    MALARIAL   FEVERS. 


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THE    AESTIVO-AUTUMNAL    MALARIAL    FEVERS.  1 99 

infection  in  this  case  without  the  aid  of  the  microscope,  and  this  case  well  il- 
lustrates the  importance  of  a  microscopical  examination  of  the  blood  in  the 
diagnosis  of  malaria.  The  prompt  subsidence  of  so  pronounced  an  infer  lion 
under  large,  repeated  doses  of  quinine  is  worthy  of  attention. 

Case  III.  Chart  8. — C.  T.  The  history  in  his  case  is  briefly  as  follows: 
The  patient  had  never  been  in  the  tropics  and  his  malaria  was  contracted  at 
Fortress  Monroe,  Va.  His  illness  began  with  a  slight  chill,  nausea,  vomiting, 
and  severe  headache  and  backache.  He  has  slight  epistaxis  and  complained  of 
some  abdominal  tenderness.     His  temperature  reached  103 .8°  after  the  chill. 

Physical  examination  showed  an  enlarged  spleen,  general  abdominal 
tenderness,  hot,  dry  skin,  flushed  face,  injected  conjunctivae,  and  a  pointed, 
tremulous  tongue  thickly  coated  with  a  white  fur;  the  pulse  was  full,  and  rather 
slow.  The  case  was  regarded  at  first  as  one  of  typhoid  fever,  but  no  Widal 
reaction  could  be  obtained,  and  an  examination  of  the  blood  showed  large 
numbers  of  quotidian  aestivo-autumnal  plasmodia. 

Examination  of  the  Blood.— The  blood  showed  numerous  intracorpus- 
cular  "ring-forms"  of  the  quotidian  aestivo-autumnal  plasmodium,  and  a  few 
crescents  {gametes).  The  intracorpuscular  plasmodia  were  very  small,  rather 
dimly  outlined,  actively  amoeboid,  and  corpuscules  showing  double  infection 
were  numerous.  The  infected  corpuscles  were  smaller  than  normal,  dark 
green  in  color,  and  often  crenated.     No  pigmented  forms  were  observed. 

The  gametes  were  remarkable  because  of  their  plump  appearance  and 
small  size;  while  the  male  and  female  organisms  could  be  distinguished,  both 
were  much  more  plump  than  the  gametes  of  the  tertian  aestivo-autumnal 
Plasmodium.  They  contained  perfectly  motionless,  almost  black  t  pigment, 
in  the  form  of  short  rods;  their  protoplasm  had  a  peculiar  refractive  ground- 
glass  appearance,  and  in  every  instance  a  darker  colored,  greenish  double  out- 
line was  to  be  seen  surrounding  them. 

Treatment. — Quinine  in  grm.  0.40  doses,  given  every  four  hours,  caused 
a  disappearance  of  the  fever  in  two  days. 

In  this  case  the  temperature  chart  is  not  as  typical  as  in  the  other  cases 
cited,  and  is  therefore  more  interesting.  During  the  first  two  days  of  the  illness 
the  temperature  showed  hardly  any  remission,  but  after  that  the  remissions 
occurred  as  usual.  It  is  difficult  to  explain  this  by  any  other  hypothesis  than  a 
double  infection  at  first,  two  groups  of  plasmodia  reaching  maturity  within  a 
few  hours  of  one  another,  one  group  afterward  dying  out.  This  explanation  is 
further  strengthened  by  the  fact  that  on  the  twenty-seventh,  two  paroxysms 
occurred,  and  by  the  presence  of  gametes  in  the  blood,  thus  showing  that  a 
malarial  infection  must  have  existed  in  a  latent  condition  for  some  time.  Upon 
the  twenty-seventh,  the  last  paroxysm  occurred  immedately  after  the  remission 
of  the  first.  As  a  whole,  however,  the  chart  is  a  fairly  typical  one  of  quotidian 
aestivo-autumnal  fever,  and  illustrates  the  value  of  the  microscopical  examina- 
tion of  the  blood,  as  this  case  resembled  so  closely  a  case  of  typhoid  fever  that  it 
was  so  diagnosed  by  every  physician  who  saw  it,  and  even  the  microscopical 


200 


THE    AESTIVCHAUTUMNAL    MALARIAL    FEVERS. 


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THE    AESTIVO-AUTUMNAL    MALARIAL    FEVERS.  201 

examination  was  considered  as  only  showing  a  malarial  complication  until  the 
rapid  disappearance  of  the  fever  under  quinine  proved  conclusively  the  malarial 
nature  of  the  infection. 

Case  IV.  Chart  9. — R.  S.  This  patient,  a  soldier,  had  been  in  the  service 
for  thirteen  years,  during  which  time  he  had  enjoyed  good  health.  He  had  had 
a  slight  cough  at  times  during  the  past  two  years,  but  there  were  no  physical 
signs  and  the  sputum  was  negative  for  Bacillus  tuberculosis.  While  in  Tampa, 
Florida,  in  1898,  he  suffered  from  chills,  occurring  every  day,  but  this  attack 
ended  after  four  days,  and  he  went  with  his  regiment  to  Santiago.  He  remained 
there  until  January,  1899,  and  suffered  from  several  attacks  of  malaria,  being 
unfit  for  duty  for  about  six  weeks  in  all.  He  arrived  at  the  hospital  at  Fortress 
Monroe  on  January  23,  1899.  While  in  the  hospital  he  developed  a  quotidian 
temperature  with  slight  chilly  sensations,  rarely  a  distinct  chill,  which  was  con- 
sidered for  a  while  to  be  due  to  tuberculosis.  At  the  time  of  the  paroxysms  he 
complained  of  headache,  pain  in  the  back  and  limbs,  and  slight  nausea.  He 
had  no  distinct  sweats. 

Physical  Examination. — Patient  somewhat  emaciated  and  very  anaemic; 
skin  bronzed  and  rather  moist;  tongue  flabby  and  coated;  spleen  enlarged; 
heart  and  lungs  normal;  abdomen  rather  tender;  pulse  full  and  rapid. 

Examination  of  the  Blood. — The  blood  contained  numerous  ring-forms 
of  the  quotidian  aestivo-autumnal  plasmodium  and  a  few  gametes  (crescents) . 
In  several  examinations  only  two  pigmented  plasmodia  were  seen. 

The  ring-forms  were  similar  in  appearance  to  those  already  described, 
being  minute  in  size  and  always  perfectly  round.  The  pigmented  forms  were 
circular  in  shape,  more  sharply  outlined  than  the  "rings,"  and  the  pigment 
consisted  of  one  black  dot  situated  in  the  center  of  the  parasite. 

The  infected  corpuscles  were  very  dark  green  in  color.  The  gametes  were 
small  and  very  plump  and  presented  a  double  outline.  An  intracorpuscular 
crescent  was  observed  during  one  examination. 

Treatment. — Quinine  in  doses  of  grm.  0.40  every  four  hours  reduced  the 
temperature  promptly. 

The  temperature  curve  in  this  case  is  remarkable  for  its  regularity,  and 
because  of  its  resemblance  to  the  temperature  curve  often  observed  in  pulmonary 
tuberculosis.  This  resemblance,  together  with  an  acute  bronchitis  which  was 
present,  led  to  the  case  being  considered  one  of  phthisis  until  a  microscopical 
examination  and  the  blood  cleared  up  the  diagnosis,  and  quinine  cured  the 
infection.  It  will  be  observed  that  the  temperature  fell  below  normal  after 
each  paroxysm.  » 

Case  V.  Chart  10. — C.  S.  The  patient  went  with  his  regiment  to  Santi- 
ago in  August,  1898.  He  was  there  about  three  weeks  when  he  was  taken  sud- 
denly ill  with  "fainting  spells,"  as  he  expressed  it.  He  was  taken  to  the  hos- 
pital and  there  suffered  from  severe  headache,  slight  chills,  and  nausea  and 
night  sweats.  Was  in  the  hospital  about  two  weeks  and  was  then  returned  to 
duty,  but  had  several  relapses,  the  last  one  occurring  about  five  weeks  before 


202 


THE    AESTIVO-AUTUMNAL    MALARIAL    FEVERS. 


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THE   AESTTVO-AUTUMNAL    MALARIAL    FEVERS.  203 

arrival  at  the  Fortress  Monroe  hospital  where  he  arrived  on  December  11,  1898, 
and  where  I  first  saw  him.  While  at  the  latter  hospital  he  suffered  from  two 
attacks  of  fever  attended  with  chilly  sentsations,  severe  headache,  and  nausea. 

Physical  Examination. — Patient  somewhat  emaciated  and  very  anaemic: 
skin  yellow;  tongue  flabby  and  coated;  heart  and  lungs  normal;  spleen  not  ap- 
preciably enlarged;  liver  enlarged;  abdomen  distended,  but  not  tender;  bowels 
constipated. 

Examination  or  the  Blood. — The  blood  contained  a  few  typical  "ring- 
forms"  of  the  quotidian  aestivo-autumnal  plasmodium,  the  "ring"  being  small, 
circular  in  shape,  actively  amoeboid  at  times,  and  unpigmented.  Pigmented 
forms  were  also  numerous.  These  were  more  sharply  defined  than  the  "ring- 
forms,"  were  less  than  one-fourth  the  size  of  the  infected  red  corpuscle,  and  the 
pigment  occurred  as  a  single  dot,  situated  at  the  center  or  one  side  of  the  para- 
site. The  pigment  was  perfectly  motionless  and  almost  black  in  color.  No 
amoeboid  motion  was  noticed  in  the  pigmented  forms  and  the  infected  corpusles 
were  always  shrunken  and  crenated,  and  many  "brassy"  cells  were  observed. 

Treatment. — Quinine  in  doses  of  grm.  0.40  every  four  hours  soon  reduced 
the  temperature  to  normal. 

The  temperature  chart  in  this  case  is  that  of  a  typical  quotidian  aestivo- 
autumnal  infection,  the  paroxysms  occurring  regularly,  and  the  chart  resembling 
that  of  a  double  tertian  infection.  From  the  study  of  a  large  number  of  cases 
of  this  type  of  malaria,  of  which  the  five  cases  given  are  fair  examples,  the  con- 
clusion is  inevitable  that  there  occurs  a  type  of  aestivo-autumnal  malarial  in- 
fection, characterized  by  quotidian  paroxysms,  and  by  the  occurrence  in  the 
blood  of  a  specific  plasmodium  which  completes  its  cycle  of  development  in 
man  in  approximately  24  hours.  In  blood  secured  by  puncture  of  the  spleen 
all  stages  in  the  development  of  this  plasmodium  may  be  studied,  and  each 
stage  differs  markedly  from  the  corresponding  stage  of  the  tertian  aestivo- 
autumnal  plasmodium.  I  have  not  been  able  to  demonstrate  the  existence  of 
an  unpigmented  quotidian  plasmodium,  as  described  by  Mannaberg,  Manson, 
and  others. 

Cases  of  Tertian  Aestivo-autumnal  Malaria. 

In  the  chapters  which  have  preceded  this  one  I  have  called  attention  to 
the  fact  that  the  majority  of  cases  of  aestivo-autumnal  fever  present  paroxysms 
occurring,  approximately,  every  48  hours.  These  tertian  paroxysms  are 
peculiar  in  that  while  they  occur  every  other  day,  each  paroxysm  is  prolonged 
so  that  it  lasts  considerably  over  24  hours,  and  often  almost  48  hours.  This 
type  of  malarial  fever  is  further  characterized  by  a  peculiar  temperature  curve, 
which  was  first  described  by  Marchiafava  and  Bignami,  and  which  shows  the 
following  characteristics:  a  rapid  and  sudden  rise,  a  stage  of  slight  remissions, 
a  pseudocrisis,  a  precritical  rise,  during  which  the  temperature  generally 
reaches  a  higher  point  than  it  had  previously,  and,  lastly,  the  true  crisis,  in 
which  the  temperature  rapidly  falls  to  normal  or  below. 


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THE   AESTIVO-AUTUMNAL    MALARIAL    FEVERS.  205 

This  peculiar  temperature  curve  is  presented  in  all  uncomplicated  cases 
of  tertian  aestivo-autumnal  malaria,  where  quinine  has  not  been  administered. 
In  cases  infected  with  two  groups  of  plasmodia  sporulating  at  different  times 
or  by  the  simple  tertian  or  quartan  plasmodium  or,  again,  by  both  the  quotidian 
and  tertian  aestivo-autumnal  plasmodia,  this  peculiar  temperature  curve  will 
not  be  observed,  nor  will  it  be  in  cases  which  have  received  insufficient  doses  of 
quinine  or  quinine  at  long  intervals  of  time. 

In  order,  then,  to  secure  a  typical  temperature  chart  of  tertian  aestivo- 
autumnal  fever,  we  must  have  a  patient  infected  with  a  single  group  of  plasmodia 
and  must  withhold  quinine  for  several  days.  It  is  safe  to  say  that  nearly  all 
of  the  confusion  existing  to-day  regarding  the  types  of  aestivo-autumnal 
malaria  is  due  to  one  or  two  factors;  infection  with  more  than  one  species  of 
plasmodium  or  with  more  than  one  group  of  plasmodia,  and  the  improper  and 
untimely  use  of  quinine.  The  first  factor  can  only  be  eliminated  by  the 
microscopical  examination  of  the  blood,  and  the  second  only  by  an  earnest 
scientific  spirit  upon  the  part  of  the  physician,  so  strong  that  he  will  be  willing 
to  withhold  quinine  long  enough  to  secure  a  proper  knowledge  of  the  nature 
of  the  disease  which  he  is  called  upon  to  treat.  Medicine  to-day  has  reached 
the  stage  where  the  so-called  diagnostic  terms  "intermittent"  and  "remittent" 
malarial  fevers  are  of  little  exact  meaning,  and  an  earnest  effort  should  be 
made  to  substitute  for  them,  in  medical  nomenclature,  the  more  scientific 
terms,  tertian  and  quartan  malaria,  and  quotidian  and  tertian  aestivo-autumnal 
malaria. 

The  following  cases  are  selected  from  a  large  number  because  they  are 
typical  of  tertian  aestivo-autumnal  malarial  fever,  and  I  believe  that  they 
conclusively  demonstrate  the  existence  of  this  variety  of  aestivo-autumnal  fever. 

Case  I.  Chart  n. — S.  C.  Age  23.  The  patient  arrived  at  Santiago, 
Cuba,  in  August,  1898.  On  September  20,  1898,  he  was  taken  sick  with 
a  chill,  which  was  followed  by  a  high  temperature.  He  had  chills  every  other 
day  for  several  days,  and  suffered  from  nausea  and  vomiting,  severe  headache 
and  pains  in  the  legs,  and  drenching  perspiration.  He  had  several  attacks 
during  the  next  two  months  and  was  finally  sent  to  the  Simpson  General  Hospital, 
where  he  arrived  upon  December  11,  1898.  Upon  December  17,  he  had  a 
rise  of  temperature  accompanied  by  chilly  sensations.  This  paroxysm  was 
succeeded  by  three  others,  all  accompanied  by  chilly  feelings,  severe  headache 
and  backache,  nausea,  and  great  nervous  prostration. 

Physical  Examination. — Patient  somewhat  emaciated;  skin  yellowish; 
mucous  membranes  pale;  cheeks  flushed;  eyes  bright;  tongue  broad  and 
coated;  heart  and  lungs  normal;  abdomen  rather  tender;  spleen  slightly  enlarged; 
bowels  constipated;  marked  mental  depression  and  general  debility. 

Examination  of  the  Blood. — The  blood  was  examined  at  frequent 
intervals  and  numerous  "ring-forms,"  pigmented  rings,  and  larger  pigmented 
forms  of  the  tertian  aestivo-autumnal  plasmodium  were  found.  No  segmenting 
forms  were  observed.    The  "ring-forms"  were  larger  than  those  of  the  quotidian 


206 


THE   AESTIVO-AUTUMNAL    MALARIAL   FEVERS. 


THE  AESTIVO-AUTUMNAL   MALAEIAL   FEVERS.  2C] 

aestivo-autumnal  plasmodium,  being  about  one-fourth  the  size  of  the  infected 
red  cell,  irregular  in  shape,  most  of  them  presenting  an  enlargement  at  some 
portion  of  the  periphery,  thus  causing  the  so-called  "signet-ring"  appearance. 
They  were  refractive  and  sharply  outlined,  with  clear  protoplasm,  and  having 
a  sluggish  amoeboid  motion.  The  "ring-form"  was  sometimes  lost  during  the 
movement  of  the  organism,  a  clear,  circular,  hyaline  disk  resulting.  The  infected 
red  corpuscles,  while  more  greenish  in  color  than  the  uninfected  cells,  was  not 
nearly  as  much  altered  in  appearance  as  in  the  quotidian  infections,  and  was 
seldom  crenated. 

The  pigmented  rings  and  larger  pigmented  bodies  were  present  in  small 
numbers.  The  "rings"  showed  a  few  fine  pigment  granules,  generally  in 
the  dilated  portion  of  the  ring,  and  these  granules  were  often  in  rather  rapid 
motion.     These  pigmented  rings  still  showed  considerable  amoeboid  motion. 

The  pigmented  bodies  larger  than  the  "ring-forms"  were  sharply  defined, 
the  protoplasm  being  refractive  and  finely  granular  in  appearance.  The 
pigment  was  in  the  form  of  fine  reddish-brown  granules,  and  possessed  a 
marked  vibratory  motion.  These  plasmodia  were  about  one-half  the  size 
of  the  infected  red  corpuscle,  and  some  of  them  still  showed  a  slight  amoeboid 
motility. 

Treatment. — Quinine  in  doses  of  grm.  0.40  every  four  hours,  reduced  the 
temperature  in  two  days,  and  its  continued  use  resulted  in  recovery. 

A  consideration  of  the  temperature  chart  in  this  case  shows  it  to  be  a 
beautiful  illustration  of  the  peculiar  temperature  curve  in  this  type  of  malarial 
fever.  Quinine  was  withheld  until  the  occurrence  of  the  fourth  paroxysm. 
It  will  be  seen  that  the  paroxysms  occurred  at  intervals  of  approximately 
48  hours,  and  that  the  temperature  lasted  from  36  to  40  hours,  and  the  chart 
shows  well  the  various  characteristics  of  the  curve  already  mentioned.  Taking 
the  paroxysm  of  the  twenty-first,  for  example,  we  see  beautifully  illustrated 
the  rise,  the  period  of  slight  remissions,  the  pseudocrisis,  the  precritical  rise, 
in  which  the  temperature  reaches  the  highest  point,  and,  lastly,  the  crisis,  in 
which  the  temperature  rapidly  fell  to  nearly  normal.  The  intervals  between 
the  paroxysms  were  short,  and  two  of  the  paroxysms  were  accompanied  by 
chills.  As  a  general  rule,  the  temperature  goes  to  normal  or  below,  during 
the  intervals,  but  in  this  case  it  did  not  always  do  so. 

Case  II.  Chart  12. — P.  R.  H.,  Age  21.  Patient  arrived  in  Cuba 
on  December  17,  1898.  Was  taken  sick  March  13,  1899,  with  severe  pain  in 
the  head,  chill,  high  fever,  and  nausea  and  vomiting.  Was  supposed  to  be 
suffering  from  typhoid  fever,  but  felt  better  after  a  week  in  the  hospital  and 
was  up  and  about.  On  April  6,  the  day  before  he  boarded  the  steamer  on  his  way 
to  Fortress  Monroe,  the  fever  returned,  accompanied  by  the  same  symptoms, 
He  arrived  at  the  Simpson  Hospital  upon  April  12.  He  had  four  chills  after 
arrival,  occurring  every  other  day,  but  not  very  severe,  accompanied  by  nausea 
and  vomiting,  headache,  and  pain  in  the  back  and  legs. 

Physical    Examination. — Patient   looks   very    ill.     Greatly    emaciated; 


208 


THE   AESTIV0-A1  TUMNAL    MALARIAL   FEVERS. 


H 


THE    AESTIVO-AUTUMNAL    MALARIAL    FEVERS.  2Q(J 

skin  yellow;  face  congested  and  eyes  bright;  tongue  broad  and  coated  with  a 
yellow  fur;  pulse  rather  weak  and  very  rapid;  heart  and  lungs  normal;  spleen 
slightly  enlarged;  liver  normal;  abdomen  rather  tender;  bowels  constipated. 

Examination  of  tfie  Blood. — The  blocd  was  examined  at  frequent 
intervals  and  always  showed  "ring-forms"  and  pigmented  ring-forms  of  the 
tertian  aestivo-autumnal  plasmodium,  similar  in  every  respect  to  those  described 
in  the  preceding  case.  No  segmenting  forms  or  crescents  were  found  in  the 
peripheral  blood.  The  parasites  were  most  numerous  just  before  the 
paroxysms. 

Treatment. — Quinine,  grm.  0.50  every  six  hours.   Recovery. 

The  temperature  chart  in  this  case  is  a  typical  one  of  tertian  aestivo- 
autumnal  fever.  It  will  be  seen  that  there  were  four  paroxysms  in  all,  and  that 
each  paroxysm  showed  the  characteristic  temperature  curve,  although  the 
paroxysm  of  the  twenty-third  is  slightly  atypical,  in  that  after  the  pseudo- 
crisis  there  occurred  a  slight  remission  before  the  final  rise  and  crisis.  In  no 
other  malarial  fever  will  a  temperature  chart  like  this  be  observed,  and  it  is 
actually  diagnostic  of  the  type  of  infection  which  it  occurs  in. 

Case  III.  Chart  13. — A.  H.  H.  The  patient,  while  in  Santiago,  suffered 
from  malarial  fever,  having  chills  nearly  every  other  day,  accompanied  by 
high  fever,  severe  headache  and  backache,  and  nausea.  He  arrived  at  Fortress 
Monroe  on  January  23,  1899,  and  after  admission  to  hospital  had  several 
paroxysms  of  fever,  accompanied  by  chilly  feelings,  but  no  distinct  chill;  severe 
headache  and  backache,  some  nausea,  and  general  muscular  pain. 

Physical  Examination. — The  patient  does  not  look  very  sick.  There  is 
some  anaemia;  the  tongue  is  coated;  the  heart,  lungs,  and  liver  are  apparently 
normal.  The  spleen  is  enlarged,  reaching  half-way  to  the  umbilicus.  There  is 
much  mental  depression. 

Examination  of  the  Blood. — The  blood  was  examined  frequently  and 
numerous  pigmented  and  unpigmented  tertian  aestivo-autumnal  plasmodia 
were  found,  most  numerous  just  before  or  some  time  after  the  paroxysm.  No 
sporulating  parasites  were  observed. 

Treatment. — Quinine,  grm.  0.40  every  four  hours.     Recovery. 

In  this  case  the  temperature  chart  is  again  typical  of  tertian  aestivo-autum- 
nal infections,  and  would  easily  be  recognized  as  such  upon  simple  inspection. 
The  occurrence  of  the  paroxysm  upon  every  third  day;  the  length  of  the  indi- 
vidual paroxysm;  the  peculiar  curve  exhibited — all  prove  conclusively  the  type 
of  malarial  fever  present,  even  without  the  aid  afforded  by  the  microscope  in 
detecting  the  characteristic  plasmodium. 

Case  IV.  Chart  14.— S.  The  patient  arrived  at  Santiago,  Cuba,  in 
August,  1898.  He  was  there  about  two  weeks  when  he  was  taken  suddenly  ill, 
having  a  chill,  high  fever,  nausea  and  vomiting,  and  great  mental  depression. 
Chills  recurred  every  other  day  and  were  always  accompanied  by  intense 
headache  and  fever.  Arrived  at  the  Simpson  U.  S.  Army  General  Hospital  on 
December  11,  1898,  and  on  the  sixteenth,  had  chilly  sensations  and  a  rise  of 
14 


2IO 


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THE   AESTIVO-AUTUMNAL    MALARIAL    FEVERS. 


211 


212  THE    AESTIVO-AUTUMXAL    MALARIAL    FEVERS. 

temperature.     He  had  two  paroxysms  after  this,  accompanied  by  fever,  intense 
headache,  nausea,  general  muscular  pain,  and  mental  depression. 

Physical  Examination. — Patient  anaemic  and  listless.  Skin  slightly 
yellow,  tongue  slightly  coated;  heart,  lungs,  and  liver  apparently  normal. 
Spleen  not  appreciably  enlarged.  Bowels  constipated.  Pulse  full  and 
regular. 

Examination  of  the  Blood. — Numerous  examinations  of  the  blood  were 
made  and  pigmented  and  unpigmented  forms  of  the  tertian  aestivo-autumnal 
Plasmodium  were  found,  and  several  segmenting  forms  were  observed  in  the 
peripheral  blocd.  The  pigmented  and  unpigmented  ring-forms  have  already 
been  described  under  Case  I.  The  large  pigmented  parasites  were  nearly 
half  as  large  as  the  infected  red  corpuscle,  and  contained  numerous  fine  granules 
of  pigment,  generally  collected  near  the  center  of  the  organism.  The  parasites 
were  very  sharply  defined  and  very  refractive.  In  some  of  the  pigmented  forms 
the  pigment  was  collected  in  a  solid  block  at  the  center  of  the  organism,  and 
faint  radial  striations  could  be  made  out  dividing  the  parasite  into  several 
segments. 

The  segmenting  forms  observed  appeared  to  be  extracorpuscular,  and  con- 
sisted of  blocks  of  pigment  with  ten  or  more  minute  oval  spores  arranged  about 
them. 

Treatment. — Quinine,  grm.  0.40  every  four  hours.     Recovery. 

The  temperature  chart  in  this  case  is  interesting  in  that  each  of  the  par- 
oxysms presents  a  modification  of  the  typical  aestivo-autumnal  curve.  In  the 
first  paroyxsm  there  is  no  stage  of  slight  remissions,  there  being  a  rapid  initial 
rise  and  almost  immediately  a  pseudocrisis,  in  which  the  temperature  reached 
normal;  this  was  immediately  succeeded  by  the  precritical  rise  and  followed 
by  the  crisis.  In  the  second  paroxysm  there  is  also  no  stage  of  slight  remis- 
sions, but  the  pseudocrisis  is  more  normal  and  the  precritical  rise  more 
gradual.  The  third  paroxysm  is  marked  by  a  well-defined  stage  of  slight 
remissions,  but  the  pseudocrisis  is  almost  absent. 

Such  slight  modifications  as  these  are  very  common  in  the  temperature 
curve  of  tertian  aestivo-autumnal  fever,  but  they  do  not  in  the  least  affect  the 
general  character  of  the  curve  nor  cause  a  moment's  doubt  as  to  the  nature  of  a 
case  showing  such  a  temperature  curve  as  is  here  presented.  Such  curves  are 
uniquely  characteristic  of  the  tertian  aestivo-autumnal  infections. 

Case  V.  Chart  15. — C.  C.  Age  25.  Arrived  at  Santiago,  Cuba,  in 
August,  1898.  Was  there  about  one  month,  when  he  had  a  sharp  chill  followed 
by  a  high  temperature.  Chills  occurred  for  a  while  every  other  day,  but  later 
became  irregular.  They  were  always  followed  by  a  high  temperature.  He 
was  admitted  to  the  hospital  there  five  different  times,  each  apparent  recovery 
from  the  fever  being  followed  by  a  relapse  as  soon  as  he  returned  to  duty. 
During  the  paroxysms  he  suffered  from  headache,  very  severe  in  character; 
severe  muscular  pains;  nausea  and  vomiting.  He  arrived  at  the  Simpson 
Hospital  on  December  11,  1898.     Had  chilly  sensations  and  a  headache  on  the 


THE    AESTIVO-AUTUMNAL    MALARIAL    FEVERS. 


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214  THE   AESTIVO-AUTUMNAL    MALARIAL    FEVERS. 

fifteenth,  followed  by  a  rise  in  temperature.  He  had  three  slight  paroxysms 
afterward,  accompanied  by  chilly  sensations. 

Physical  Examination. — Patient  emaciated  and  anaemic.  Skin  yellow, 
tongue  flabby  and  coated.  Heart  and  lungs  normal.  Spleen  greatly  enlarged, 
reaching  nearly  to  the  umbilicus.  Liver  dullness  normal.  Bowels  constipated. 
.Abdomen  tender. 

Examination  of  the  Blood. — The  blood  in  this  case  showed  pigmented 
"ring-forms"  of  the  aestivo-autumnal  plasmodium  and  numerous  gametes 
(crescents).  The  ring-forms  were  similar  to  those  described  as  occurring  in 
Case  I.  The  gametes,  both  male  and  female,  were  very  much  more  slender 
and  much  larger  than  those  of  the  quotidian  aestivo-autumnal  plasmodium, 
and  contained  a  much  greater  amount  of  pigment  of  a  more  reddish  color. 
The  double  outline  was  less  commonly  observed,  but  the  protoplasm  was 
much  more  refractive. 

In  this  case  the  temperature  chart  is  not  as  typical  as  the  preceding  ones, 
but  it  is  typical  of  the  more  chronic  forms  of  tertian  aestivo-autumnal  infection. 
The  paroxysms  occur  every  48  hours,  but  it  is  noticeable  that  the  range  of 
temperature  is  not  as  high  in  this  case  and  that  there  seems  to  be  a  tendency 
toward  a  spontaneous  decline  of  the  infection.  The  chart  is  curious  in  that 
there  seems  to  be  a  reversal  of  the  ordinary  temperature  curve,  the  highest 
temperature  being  reached  during  the  initial  rise;  but  even  in  this  chart  the 
temperature  curve  is,  on  the  whole,  so  characteristic  that  a  diagnosis  of  tertian 
aestivo-autumnal  fever  could  easily  be  made  from  an  inspection  of  it 

From  the  cases  of  quotidian  and  tertian  aestivo-autumnal  malarial  fever 
I  have  here  considered  it  will  be  seen  that  a  differentiation  of  the  two  types 
cannot  be  made  from  a  consideration  of  the  clinical  symptoms  except  that  in 
the  quotidian  form  the  chill  or  chilly  sensations  occur  every  24  hours,  while 
in  the  tertian  form  they  occur  every  48  hours.  A  consideration  of  the  tem- 
perature charts,  however,  shows  such  a  marked  difference  in  the  temperature 
curves  that  we  must  admit  that  we  are  dealing  with  two  distinct  types  of  malarial 
infection.  The  quotidian  aestivo-autumnal  type  presents  a  simple  intermittent 
temperature  curve,  indistinguishable  from  that  of  a  double  tertian  infection, 
while  the  tertian  aestivo-autumnal  infections  present  a  most  peculiar  and 
characteristic  temperature  curve,  entirely  different  from  that  shown  in  any 
other  type  of  malarial  infection  and  diagnostic  in  itself.  When  to  this  is  added 
the  fact  that  each  form  is  due  to  a  specific  plasmodium,  one  sporulating  in 
24  hours,  the  other  in  48  hours,  the  evidence  is  complete  that  there  occur  two 
forms  of  aestivo-autumnal  malarial  fever,  the  tertian  and  quotidian,  as  first 
described  by  Marchiafava  and  Bignami. 

In  the  study  of  these  infections  it  is  absolutely  necessary  that  the  tempera- 
ture be  recorded  every  three  or  four  hours,  as,  in  many  cases,  a  morning  and 
evening  record  of  the  temperature  will  give  but  little  information  regarding  the 
actual  range  of  the  fever. 


CHAPTER  III. 
The  Pernicious  Forms  of  the  Malarial  Fevers. 

The  term  "pernicious"  as  used  in  the  nomenclature  of  malaria  indicates 
infections  in  which  some  one  symptom  or  group  of  symptoms  so  preponderate 
as  to  color  the  clinical  picture  and  threaten  the  life  of  the  patient.  Used  in 
this  sense,  the  term  is  of  value  in  clinical  work,  but  unfortunately  some  writers 
have  considered  the  pernicious  forms  of  malaria  as  disease  entities  and  have 
used  the  term  to  designate  certain  infections,  especially  the  aestivo-autumnal 
fevers.  With  these  writers  pernicious  malarial  fevers  mean  the  aestivo- 
autumnal  infections  and  the  use  of  the  term  becomes  essential  in  designating 
this  group  of  fevers.  A  classification  based  upon  the  severity  of  the  symptoms 
present  in  any  given  disease  is  unscientific  and  confusing,  and  is  especially 
so  in  the  malarial  infections,  which  are  due  to  different  species  of  plasmodia. 
Mannaberg  says,  regarding  the  classification  of  malaria  into  pernicious  and 
benign  forms:  "We  search  pathology  in  vain  for  an  analogy.  As  far  as  I 
know,  there  is  no  other  disease,  though  it  runs  its  course  sometimes  smoothly  and 
without  prognostic  danger,  again  under  the  severest  and  most  threatening 
symptoms,  for  which  a  division  into  benign  and  pernicious  had  been  made. 
If  we  were  to  follow  out  this  division,  we  should  speak  of  a  benign  typhoid 
fever  when  the  disease  was  mild,  of  a  pernicious  typhoid  fever  when,  in  its 
evolution,  dangerous  symptoms  arose.  There  would  be,  in  addition,  an  endless 
series  of  sub-divisions,  depending  on  whether  the  dangerous  symptoms  proceeded 
from  one  or  another  organ."  This  criticism  of  Mannaberg's  is  just,  but 
while  the  term  should  not  be  used  to  designate  disease  entities,  it  is  of  value 
as  a  convenient  clinical  term  in  designating  malarial  infections  of  great  severity 
and  in  which  certain  symptoms  arise  which  serve  to  distinguish  them  from 
the  ordinary  type  of  infection.  The  term  cannot  be  considered  accurate, 
as  what  shall  be  considered  pernicious  symptoms  will  always  depend  upon  the 
opinion  of  the  physician,  and  this  will,  of  course,  vary  greatly  in  individual 
instances. 

It  should  be  distinctly  understood  that  there  is  no  species  of  plasmodium 
which  produces  only  pernicious  forms  of  malaria,  but  that  the  same  species 
which  causes  the  mildest  infections  is  also  capable  of  causing  rapidly  fatal 
forms.  Any  of  the  species  of  malarial  plasmodia  may  give  rise  to  pernicious 
symptoms,  but  the  vast  majority  of  fatal  cases  of  malarial  fever  are  due  to  the 
tertian  aestivo-autumnal  plasmodium,  the  next  most  frequent  parasite  being 
the  quotidian  aestivo-autumnal  plasmodium.  As  the  greater  number  of  fatal 
cases  of  malaria  occur  in  patients  infected  with  the  aestivo-autumnal  plasmodia, 

215 


2l6  THE    PERNICIOUS    MALARIAL    FEVERS. 

it  is  very  important  to  remember  that  there  is  always  an  element  of  danger  in 
these  cases,  in  that  they  may  at  any  time  develop  pernicious  symptoms  which 
may  cause  the  death  of  the  patient. 

The  great  majority  of  pernicious  attacks  of  malaria  occur  in  temperate 
regions  in  the  late  summer  and  in  autumn  and  are  rare,  while  in  the  tropics 
they  occur  throughout  the  year  and  are  very  common.  The  frequency  of 
occurrence  of  such  infections,  as  given  by  various  authors,  varies  greatly, 
depending  upon  the  locality  in  which  the  observer  was  working,  the  season  of 
the  year  in  which  the  observations  were  made,  and  the  number  of  cases  of 
malarial  infection  observed.  Thus  Borius,  in  Senegal,  in  ioo  cases  of  aestivo- 
autumnal  malaria,  observed  4.1  per  cent,  of  pernicious  cases;  Laveran,  in 
Algiers,  a  proportion  of  1  pernicious  case  to  35  others,  and  A.  Plehn,  in  the 
Kamerun,  a  proportion  of  one  pernicious  case  to  eight  in  which  the  symptoms 
were  benign.  In  temperate  regions  the  proportion  is  nil  in  some  localities  and 
very  small  in  almost  all  regions  in  which  the  aestivo-autumnal  infections  occur 
but  rarely.  In  my  own  experience,  embracing  the  study  of  several  thousand 
cases  of  malaria  contracted  in  Cuba  and  the  Philippine  Islands,  the  proportion 
of  pernicious  cases  has  not  been  over  1  to  100,  but  most  of  these  infections  were 
treated  promptly  with  quinine,  which,  of  course,  resulted  in  a  smaller  number 
of  pernicious  attacks. 

As  a  rule,  pernicious  symptoms  develop  only  after  repeated  attacks  of 
the  infection,  although  I  have  seen  more  than  one  instance  in  which  the  patient 
was  struck  down,  as  by  lightning,  with  a  pernicious  attack  of  malaria,  but  in 
which  no  history  of  a  previous  infection  could  be  obtained.  However,  the 
great  majority  of  pernicious  attacks  occur  in  persons  who  have  suffered  repeatedly 
from  malarial  paroxysms  which  have  not  been  properly  treated,  and  the 
pernicious  symptoms  often  develop,  in  such  cases,  during  an  apparently  mild 
paroxysm. 

The  Causes  of  Perniciousness. — Why  do  certain  cases  of  malarial  infec- 
tion develop  pernicious  and  fatal  symptoms  ?  In  answer  we  must  admit  that 
our  knowledge  is,  as  yet,  incomplete,  but  individual  susceptibility  to  the  in- 
fection; certain  preexisting  diseases  of  the  viscera;  external  conditions,  as 
regards  locality,  exposure,  and  poverty;  and  the  species  and  number  of  the 
infecting  plasmodia,  all  undoubtedly  help  to  explain  the  occurrence  of  such 
cases. 

Some  individuals  appear  to  be  very  susceptible  to  the  malarial  poison  and 
always  suffer  from  pernicious  attacks,  while,  on  the  other  hand,  an  individual 
but  little  affected  usually  may  suddenly  develop  pernicious  symptoms.  Alco- 
holics, and  those  weakened  by  disease,  exposure,  and  lack  of  proper  food,  are  es- 
pecially apt  to  suffer  from  pernicious  attacks  of  malaria.  I  have  repeatedly 
observed  the  occurrence  of  pernicious  symptoms  in  soldiers  who  have  been 
exposed  for  too  long  a  time  to  the  tropical  sun,  and  some  of  the  most  severe 
cases  of  cerebral  pernicious  malaria  that  I  have  observed  have  developed  sud- 
denly in  soldiers  upon  the  march  in  the  tropics.     Europeans  are  said  to  suffer 


THE    PERNICIOUS    MALARIAL    FEVERS.  217 

more  frequently  from  pernicious  attacks  than  natives,  and  while  this  is  gener- 
ally true,  there  are  exceptions,  as  at  Camp  Stotsenburg,  in  the  Philippines, 
where  pernicious  cases  were  more  common  among  the  natives  than  among  our 
soldiers  in  the  proportion  of  four  to  one. 

As  has  been  stated,  the  species  of  Plasmodium  is  of  importance,  as  most 
pernicious  attacks  are  due  to  the  aestivo-autumnal  plasmodia,  especially  the 
tertian  form.  However,  we  now  have  the  records  of  many  cases  of  pernicious 
malaria  caused  by  the  simple  tertian  and  the  quartan  plasmodium,  and  the 
statement  of  Mannaberg  that  these  organisms  cannot  cause  pernicious  symp- 
toms can  no  longer  be  accepted.  In  the  tropics  the  aestivo-autumnal  infections 
are  more  apt  to  become  pernicious  than  in  temperate  regions,  probably  because 
of  the  debility  and  anaemia  so  common  in  tropical  regions,  and  the  climatic 
conditions  there  present. 

The  number  of  plasmodia  present  in  any  given  case  must  have  great  influ- 
ence in  the  production  of  pernicious  symptoms,  and  it  has  been  definitely 
proven  that  in  pernicious  infections  the  plasmodia  are  always  more  numerous 
than  they  are  in  mild  infections.  The  increased  number  of  plasmodia  is  not, 
by  any  means,  manifest  in  an  examination  of  the  peripheral  blood,  for  in  the 
aestivo-autumnal  infections,  which  furnish  the  majority  of  pernicious  cases, 
the  plasmodia  are  frequently  small  in  number  in  the  peripheral  blood, 
but  occur  in  immense  numbers  in  the  viscera,  especially  in  the  brain  and  the 
spleen.  Thus  we  can  place  but  little  dependence  upon  the  number  of  plasmodia 
observed  in  the  peripheral  blood  as  indicating  the  severity  of  the  infection  in 
many  instances,  but  in  such  cases  a  splenic  puncture  will  demonstrate  innumer- 
able plasmodia  to  be  present  in  that  organ.  I  recall  a  case  of  fatal  aestivo- 
autumnal  infection  in  which  the  examination  of  the  peripheral  blood  resulted  in 
finding  only  three  or  four  plasmodia  after  half  an  hour's  search,  but  at  autopsy 
smears  from  the  brain  and  the  spleen  showed  so  many  plasmodia  that  it  was 
almost  impossible  to  find  an  uninfected  red  corpuscle.  In  the  cerebral  types 
of  pernicious  malaria  the  capillaries  of  the  brain  are  always  found  crowded 
with  plasmodia,  although  the  examination  of  the  peripheral  blood  may  have 
shown  but  few  plasmodia. 

Although  we  have  no  reliable  data  at  present  concerning  the  malarial 
toxin,  it  is  but  reasonable  to  suppose  that  a  more  powerful  toxin  is  elaborated 
in  the  pernicious  infections,  or  better,  perhaps,  that  a  greater  amount  is  pro- 
duced because  of  the  increase  in  the  number  of  plasmodia. 

The  situation  of  the  plasmodia  has  certainly  something  to  do  with  the  pro- 
duction of  pernicious  symptoms.  Bastianelli  and  Bignami  have  carefully 
studied  this  subject,  and  make  the  following  distinctions  as  regards  distribution 
of  the  plasmodia  and  the  symptoms  produced  by  them: 

"1.  Cases  in  which  the  number  of  parasites  is  most  abundant,  yes,  enor- 
mous, in  the  brain,  while  all  the  organs  are  less  uniformly  invaded.  These 
are  the  commonest  forms  of  pernicious  malaria,  and  are  usually  accompanied  by 
coma. 


2l8  THE    PERNICIOUS    MALARIAL    FEVERS. 

"There  are  some  cases  in  this  category  in  which  the  number  of  parasites 
in  the  blood  of  the  finger,  of  the  spleen,  of  the  bone-marrow,  etc.,  is  enormous, 
while  the  number  in  the  brain  is  scanty.  Clinically,  the  absence  of  cerebral  phe- 
nomena is  noted. 

"2.  Cases  in  which  the  number  of  organisms  is  absolutely  and  relatively 
scanty  in  the  bone-marrow,  the  spleen,  and  in  the  liver,  while  they  may  be  rela- 
tively few  in  the  blood  of  the  finger,  and  yet  other  organs  are  crowded  with  them. 
Among  these  the  following  localizations  are  to  be  made  out: 

"a.  The  brain  and  the  meninges  are  filled  with  parasites,  either  in  sporula- 
tion  or  in  all  their  stages  of  development.  Clinically,  there  are  cerebral  phe- 
nomena. 

"b.  The  stomach  and  intestines  are  chiefly  invaded.  In  these  organs  the 
mature  forms  of  the  parasites  are  usually  found;  these  are  the  cases  of  pernicious 
fever  which  present  clinically  intestinal  phenomena." 

Some  authorities  have  endeavored  to  prove  that  the  increased  fever  ob- 
served in  many  cases  of  pernicious  malaria  is  responsible  for  the  occurrence 
of  the  pernicious  symptoms,  but  this  is  disproven  by  the  fact  that  many 
cases  of  pernicious  malaria  do  not  prevent  any  increase  in  fever  as  usually 
observed  in  malarial  infections,  and  some  cases  occur  in  which  the  fever  is 
so  slight  as  to  hardly  attract  attention. 

Classification  of  Pernicious  Fevers. — The  pernicious  forms  of  malaria 
may  be  classified  in  three  ways,  i.e.,  from  the  species  of  plasmodium  causing 
them,  as  tertian,  quartan,  and  aestivo-autumnal  pernicious  infections;  from  the 
character  of  the  temperature  curve,  as  tertian,  quartan,  remittent  and  larval 
infections;  and  from  the  most  prominent  symptoms  present.  Under  the  latter 
classification  we  may  have  comatose,  delirious,  tetanic,  eclamptic,  hemiplegia, 
dysenteric,  choleraic,  algid,  cardialgic,  hemorrhagic,  pneumonic,  bilious,  and 
tvphoidal  pernicious  fevers. 

I  shall  describe  the  more  important  forms,  using  the  terms  applied  to  them 
because  of  their  most  prominent  symptoms,  but  it  must  be  remembered  that 
these  forms  are  not  disease  entities,  and  are  classified  in  this  manner  only  for 
purposes  of  clinical  description. 

Comatose  Pernicious  Form. — This  is  the  most  common  form  of  perni- 
cious malarial  fever,  and  occurs  in  two  ways,  either  as  a  sudden  attack  of  coma 
or  a  gradually  developing  comatose  condition  during  a  paroxysm  of  fever. 

The  sudden  development  of  coma  is  rare  and,  unless  at  once  recognized 
and  treated,  invariably  fatal.  In  this  form  the  patient,  who  has  generally 
suffered  from  repeated  attacks  of  malaria  and  who  has  not  felt  well  for  some 
time,  is  suddenly  stricken  with  profound  coma,  falls  to  the  ground,  and  in 
fatal  cases  does  not  again  regain  consciousness.  This  form  is  apt  to  be  mistaken 
for  apoplexy  or  sun-stroke.  The  face  is  suffused,  the  pupils  contracted,  the 
pulse  at  first  full  and  bounding,  later  soft,  rapicl,  and  thready,  the  respirations 
hurried  and  sometimes  stertorous.  The  temperature  is  irregular,  seldom 
reaching  1030  F.,  and  is  often  subnormal.  Death  generally  occurs  within 
two  days. 


THE    PERNICIOUS    MALARIAL    FEVERS.  2IQ 

The  most  common  form  of  comatose  malaria  is  that  in  which  coma  develops 
more  or  less  gradually  during  an  attack  of  the  fever.  The  symptomatology 
of  the  attack  is  the  same  as  in  the  ordinary  paroxysm,  but  the  nervous  symp- 
toms, such  as  restlessness  and  delirium,  may  be  more  marked.  As  a  rule, 
the  patient  is  restless  and  mentally  depressed.  Following  this  there  develops 
a  tendency  to  somnolence,  which  deepens  into  stupor  and  finally  coma.  Uncon- 
sciousness is  complete,  the  patient  lying  perfectly  quiet,  or  there  may  be  restless 
movements  of  the  arms  and  legs.  The  skin  is  often  somewhat  icteric  in  hue, 
and  hot  and  dry;  the  pupils  are  generally  equally  contracted,  but  may  be  unequal 
or  equally  dilated.  The  icteric  hue,  which  is  often  present  in  the  conjunctivae, 
has  led  to  a  diagnosis  of  yellow  fever  in  infected  regions.  The  face  may  be 
cyanotic,  but  in  old  infections  it  is  generally  pale.  Slight  spasms  of  the  muscles 
of  the  face  are  not  infrequent.  The  tongue  is  tremulous,  dry,  and  thickly 
coated,  and  slight  hemorrhages  into  the  skin  are  sometimes  observed. 
There  may  be  hemiplegia  or  total  paralysis.  The  patellar  reflex  may  be 
absent  or  slightly  increased.  The  respirations  are  generally  slow  and  quiet, 
but  may  be  rapid,  irregular,  or  stertorous.  The  Cheyne-Stokes  type  of 
respiration  is  sometimes  observed.  The  pulse  is  generally  slow,  full,  and 
incompressible  at  first,  but  becomes  rapid  and  weak  as  the  paroxysm  progresses. 
The  faeces  and  urine  are  passed  involuntarily  toward  the  last,  and  retention  of 
urine  may  occur.  In  cases  having  a  fatal  termination,  the  pulse  becomes 
thready,  rapid,  and  irregular;  the  respirations  intermittent,  labored,  and 
shallow;  the  skin  pale  and  bedewed  with  a  cold  perspiration;  the  features  pale, 
shrunken,  apparently  emaciated,  and  death  occurs  by  collapse.  In  cases 
which  recover,  the  temperature  falls,  accompanied  by  perspiration  and  the 
consciousness  is  slowly  regained,  but  in  many  of  these  cases  the  improvement 
is  only  apparent  and  the  patient  relapses  in  the  course  of  a  few  hours  into  a 
second  paroxysm,  and  perhaps  into  a  third,  which  usually  results  fatally. 
Between  the  paroxysms  the  mental  condition  is  one  of  torpor  or  great  mental 
depression,  accompanied  by  severe  headache.  The  duration  of  the  coma  is 
variable,  lasting  from  a  few  hours  to  three  or  four  days,  but  it  generally  does 
not  persist  longer  than  24  to  26  hours. 

As  regards  the  course  of  the  temperature  in  this  form  of  malaria,  it  may 
be  stated  that  it  is  irregular.  Some  patients  have  a  high  fever  throughout, 
between  1030  and  io4°F.,  while  in  others  the  temperature  may  remain  slightly 
above  normal,  or  may  be  subnormal  most  of  the  time.  In  fatal  cases  the 
fever,  if  present,  declines,  as  a  rule,  some  hours  before  death,  but  it  may  ascend. 
Manson  cites  temperatures  of  no°  and  1120  F.  before  death. 

As  an  illustration  of  how  low  the  temperature  may  run  the  following 
temperature  record  of  a  fatal  case  of  quotidian  aestivo-autumnal  fever,  of 
the  comatose  type,  is  of  interest.  This  case  was  under  my  personal  observation 
and  was  in  the  person  of  a  soldier  who  had  returned  from  the  Philippine 
Islands  infected  with  malaria. 


220  the  pernicious  malarial  fevers. 

Temperature  Record. 

July  15,  a.  m.,  98. 40  F.;  p.  m.,  ioi°  F. 

July  16,  a.  m.,  Q90  F.;  p.  m.,  99. 6°  F. 

July   17,  A.  m.,  9S0  F.;  p.  m.,  97. 8°  F. 

July  18,  a.  m.,  96. 40  F.;  p.  m.,  980  F. 

July  19,  A.  M.,  100.  20  F.;  p.  m.,  980  F. 

July  20,  A.  M.,  1030  F.;  p.  m.,  Died. 

In  this  case  the  disease  was  not  recognized  by  the  attending  physician 
until  a  few  hours  before  death,  when  a  blood  examination  was  asked  for, 
and  large  numbers  of  quotidian  aestivo-autumnal  plasmodia  were  found. 

Other  Pernicious  Forms  of  Malaria  in  Which  Nervous  Symptoms 
Predominate. — Besides  the  comatose  form  of  pernicious  malaria  there  are 
other  forms  in  which  nervous  symptoms  predominate.  Among  these  may 
be  mentioned  the  delirious  form,  in  which  the  patient  has  hallucinations, 
followed  by  violent  excitement;  the  eclamptic  form,  which  is  common  in  children, 
in  which  the  symptoms  are  similar  to  those  of  cerebrospinal  meningitis,  there 
being  vomiting,  headache,  fever,  pain  in  the  back  of  the  neck,  convulsions, 
and  coma;  the  hemiplegia  form,  characterized  by  hemiplegia;  the  paraplegic 
form,  characterized  by  paraplegia;  and  the  amaurotic  form,  in  which,  after  the 
comatose  symptoms  have  subsided,  complete  blindness  may  result.  Among 
the  most  infrequent  forms  of  pernicious  malaria  may  be  mentioned  the  tetanic 
form,  characterized  by  trismus,  convulsions,  opisthotonos,  and  delirium, 
and  the  ataxic  form,  cases  of  which  have  been  very  thoroughly  studied  by 
Torti  and  Angelini. 

In  all  cerebral  types  of  pernicious  malaria  there  may  be  present  slight 
deviation  of  the  eye-balls  and  slight  convulsions,  clonic  in  character,  of  the 
extremities.  Epileptiform  convulsions  occur  but  rarely  in  adults,  but  are  not 
uncommon  in  children.  At  Camp  Stotsenburg  almost  every  case  of  pernicious 
malaria  that  I  observed  among  the  native  children  was  accompanied  by 
epileptiform  convulsions. 

The  Bulbar  Form  of  Pernicious  Malaria. — A  rare  form  of  pernicious 
malaria,  associated  with  symptoms  of  bulbar  paralysis  has  been  studied  by 
Marchiafava,  Bignami,  and  Bastianelli.  Marchiafava  thus  graphically 
describes  the  symptomatology  of  this  form  of  the  disease.  "The  chief  symp- 
toms are  difficulty  in  articulation,  which  may  even  reach  anarthria,  a  weak 
and  nasal  voice,  inferior  facial  paralysis  often  of  one  side  only,  a  half-open  mouth 
from  which  drops  the  saliva,  a  pendent  lower  lip,  a  dry  and  only  slightly 
movable  tongue,  difficult  or  abolished  deglutition.  With  these  symptoms  there 
are  sometimes  associated  disturbances  of  equilibrium  which  recall  the  staggering 
gait  of  cerebellar  disease.  In  a  case  of  relapse  Bastianelli  and  Bignami 
noticed  an  unsteadiness  of  gait  as  in  drunkenness,  diminution  of  strength  of 
the  left  side,  right  facial  paralysis,  deviation  of  the  tongue  to  the  left,  difficulty 
in  speaking,  nasal  voice,  grave  prostration  and  apathy." 


THE    PERNICIOUS    MALARIAL    FEVERS.  221 

The  symptoms  in  these  cases,  under  proper  treatment,  do  not  persist  for 
a  longer  period  than  two  weeks,  as  a  general  ride. 

The  Paralytic  Forms. — Malarial  infections  in  which  either  hemiplegia 
or  paraplegia  occur  are  rare,  and  I  have  observed  only  one  case  in  which 
hemiplegia  was  present.  Landouzy  has  added  much  to  our  knowledge  of 
such  infections,  and  in  his  Thesis  de  Paris,  of  1880,  has  collected  12  cases 
of  hemiplegia  occurring  during  malarial  infection,  of  which  eight  were  accom- 
panied by  aphasia.  An  intermittent  form  of  paralysis  has  been  described 
occurring  with  the  paroxysms,  and  remitting  afterward,  but  it  is  probable  that 
the  majority  of  these  cases  were  hysterical  in  character. 

The  Algid  Form.— In  certain  regions  of  the  Southern  and  Middle  States 
and  in  other  localities  there  occur  pernicious  forms  of  malaria  known  as  algid 
forms.  The  symptoms  develop  after  one  or  more  ordinary  paroxysms  or  they 
may  be  the  primary  symptoms.  The  characteristic  condition  is  one  of  extreme 
collapse  attended  by  profuse  perspiration,  the  temperature  at  the  same  time 
being  more  or  less  elevated,  although  in  some  cases  the  temperature  is  sub- 
normal. Patients  suffering  from  this  form  of  malarial  infection  present  a 
characteristic  countenance,  the  cheeks  being  drawn  and  pinched,  the  eyes 
sunken,  the  nostrils  dilated  and  the  skin  bedewed  with  perspiration.  The 
entire  body  is  cold,  the  skin  cyanotic  and  bathed  with  a  cold  sweat.  The  lips 
and  finger-nails  are  intensely  cyanotic.  The  tongue  is  tremulous,  dry,  and 
coated  with  a  dirty  white  fur.  The  pulse  is  rapid,  thready,  and  easily,  com- 
pressible, and  generally  more  or  less  intermittent;  the  heart  sounds  are  muffled 
and  the  second  sound  almost  inaudible,  and  as  death  approaches  the  pulse 
becomes  imperceptible;  the  respirations  are  irregular,  superficial  in  character, 
and  labored;  the  muscular  weakness  is  extreme,  while  the  mental  condition  of 
the  patient  is  one  of  apathy  to  his  surroundings  and  indifference  as  to  his  condi- 
tion. These  symptoms  rarely  last  over  a  few  hours,  death  generally  resulting. 
This  is  one  of  the  most  pernicious  types  of  malarial  infection  and  one  which 
is  most  resistant  to  treatment.  Such  cases  have  been  described  by  Laveran, 
Thayer,  Marchiafava,  Bignami,  Osier,  and  Sternberg.  In  one  case  observed  by 
the  writer  in  the  person  of  a  soldier  who  contracted  aestivo-autumnal  fever  in 
Cuba,  algid  symptoms  developed  and  death  occurred  in  six  hours  despite  all 
therapeutic  aid.  He  had  suffered  from  several  paroxysms  previously,  none  of 
which  were  of  great  severity  and  had  been  easily  controlled  by  quinine.  His 
blood  showed  numerous  tertian  aestivo-autumnal  plasmcdia. 

The  Choleraic  Form. — Certain  cases  of  aestivo-autumnal  infection 
present  symptoms  very  closely  simulating  those  of  Asiatic  cholera.  It  is  not  rare 
to  observe  cases  of  malaria  accompanied  by  more  or  less  diarrhoea,  but  in  cases 
presenting  the  choleraic  symptoms  the  stools  suddenly  become  watery,  very 
profuse,  and  numerous;  they  may  be  blood-  or  bile-stained,  or  almost  colorless, 
and  may  contain  mucus  in  small  flakes,  thus  resembling  the  rice-water  stool  of 
cholera.  The  profuse  diarrhoea  lends  to  collapse,  the  face  becoming  pinched, 
the  eyes  sunken,  the  skin  cold  and  clammy,  and  cyanotic  in  appearance.     The 


22  2  THE    PERNICIOUS    MALARIAL    FEVERS. 

pulse  and  respiration  become  greatly  weakened,  and  the  patient,  in  a  husky  or 
tremulous  voice,  complains  of  severe  cramps  in  the  abdomen  and  thighs  and 
intense  thirst;  he  is  greatly  worried  over  his  condition,  and  there  is  great  mental 
depression.  Death  is  the  usual  result  in  untreated  cases,  but  where  proper 
therapeutic  measures  are  employed,  the  majority  of  the  cases  will  recover. 
The  temperature  in  the  choleraic  form  is  generally  elevated.  It  is  rarely  that 
the  choleraic  symptoms  recur,  but  when  they  do  the  result  is  almost  invariably 
fatal. 

This  form  of  pernicious  aestivo-autumnal  fever  simulates  cholera  so  closely 
that  the  differentiation  is  very  difficult,  especially  in  countries  where  cholera  is 
endemic  or  epidemic.  The  recognition  of  such  cases  is  of  great  importance 
and  can  only  be  assured  by  the  microscopical  examination  of  the  blood.  Major 
Chamberlain,  of  the  U.  S.  Army,  has  recently  reported  a  most  interesting  case 
of  choleraic  pernicious  fever,  in  which  the  symptoms  were  indistinguishable 
from  those  of  cholera. 

The  Cardialgic  Form. — This  form  of  pernicious  malarial  fever  is  com- 
paratively rare,  and  is  generally  associated  in  classification  with  the  gastralgic 
form.  The  prominent  symptoms  are  severe,  agonizing  pain  in  the  epigastrium 
or  over  the  cardiac  region,  and  the  vomiting  of  matter  tinged  with  blood.  Hic- 
cough is  often  a  distressing  symptom,  and  severe  hematemesis  may  occur. 
These  symptoms  occur  during  the  febrile  paroxysm.  The  patient  presents  an 
anxious  countenance,  a  dry,  glazed  tongue,  brilliant  eyes,  a  retracted  abdomen, 
cold  extremities,  hurried  respiration,  and  a  rapid,  weak  pulse;  he  suffers  in- 
tense pain,  and  either  groans  or  calls  out  under  the  torture  which  he  is  enduring. 
In  fatal  cases  collapse  occurs,  accompanied  by  the  symptoms  of  the  algid  form. 

Laveran,  Colin,  and  Haspel  have  described  cases  of  the  cardialgic  and 
gastralgic  forms  of  pernicious  malaria.  I  have  seen  but  one  case  conforming  to 
this  type.  The  patient  was  a  soldier,  22  years  of  age,  who  had  suffered  from 
repeated  attacks  of  malaria  in  the  Philippine  Islands.  During  the  paroxysm  in 
which  I  observed  him  he  had  most  intense  pain  over  the  left  nipple  and  the 
epigastrium,  which  radiated  to  the  vertebral  column  and  down  the  thigh;  the 
pain  was  so  intense  that  screams  were  forced  from  him.  He  repeatedly  vomited 
blood-stained  fluid  and  suffered  greatly  from  hiccough.  His  temperature 
reached  103. 40  F.,  his  pulse  was  very  rapid  and  thready,  his  extremities  cold, 
and  he  complained  of  great  prostration  and  was  very  anxious  regarding  his 
condition.  Under  repeated  hypodermics  of  quinine  his  condition  gradually 
improved  and  he  eventually  recovered. 

The  Dysenteric  Form. — A  considerable  proportion  of  patients  suffering 
from  aestivo-autumnal  malaria  present  symptoms  of  dysentery,  consisting  in 
frequent  mucoid  and  bloody  stools,  tenesmus,  colicky  pain  in  the  abdomen,  and 
progressive  emaciation.  Scheube  observed  such  cases  in  Japan  and  describes 
the  malarial  paroxysms  as  accompanied  by  the  usual  symptoms  of  acute  dysen- 
tery. At  the  U.  S.  Army  General  Hospital  at  the  Presidio  of  San  Francisco, 
Cal.,  a  very  large  proportion  of  cases  of  malaria,  chiefly  of  the  aestivo-autumnal 


THE    PERNICIOUS    MALARIAL   FEVERS.  223 

variety,  presented  dysenteric  symptoms.  In  fact,  65  per  cent,  of  cases  of  un- 
recognized malaria  (before  a  blood  examination)  observed  there  were  diagnosed 
either  as  diarrhoea  or  dysentery.  This  proves  how  commonly  dysenteric 
symptoms  are  produced  by  malarial  infection,  and  it  is  undoubtedly  the  fact 
that  in  tropical  regions  a  certain  proportion  of  cases  diagnosed  as  dysentery 
are  in  reality  the  dysenteric  form  of  malarial  infection. 

There  exists  a  chronic  form  of  malarial  infection  characterized  by  the 
symptoms  usually  observed  in  chronic  dysentery,  the  patient  suffering  from 
attacks  of  diarrhoea,  pain  in  the  abdomen,  muscular  weakness,  and  loss  of  flesh 
and  strength.  This  condition  I  have  often  observed  in  soldiers  and  it  is  always 
cure  by  the  persistent  use  of  quinine.  The  proper  administration  of  this  drug  in 
multitudes  of  cases  supposed  to  be  dysenteric  nature,  until  this  was  disproven  by 
the  microscope,  has  always  resulted,  in  my  experience,  in  the  disappearance 
of  the  symptoms  and  a  return  to  health.  There  is  no  doubt  in  my  mind 
that  there  not  only  exists  an  acute,  and  sometimes  fatal  form  of  pernicious 
malaria,  characterized  by  dysenteric  symptoms,  but  that  there  is  a  form  of 
malaria,  more  chronic  in  character,  which  is  common  in  the  tropics,  which  is 
characterized  by  repeated  attacks  of  diarrhoea,  dysenteric  in  type,  and  which 
is  generally  diagnosed  by  the  practitioner  as  a  mild  form  of  dysentery. 

The  Hemorrhagic  Form.— Marchiafava  and  Laveran  have  described 
cases  of  pernicious  malarial  fever  characterized  by  severe  hemorrhages  into  the 
skin  and  mucous  membrane,  as  well  as  the  occurrence  of  hematemesis,  epistaxis, 
and  hemoptysis.  These  symptoms  may  be  so  severe  as  to  cause  death.  Another 
group  of  cases  occurs  in  which  the  hemorrhages  occur  within  the  viscera, 
especially  the  lungs,  and  some  of  the  pneumonic  malarial  infections  are  doubt- 
less explained  in  this  way.  The  temperature  is  extreme  in  most  of  these  cases, 
which  are  undoubtedly  very  rare.  Epistaxis  even  of  quite  severe  character,  is 
not,  however,  a  very  rare  symptom  in  attacks  of  aestivo-autumnal  malaria,  for  I 
have  observed  a  large  number  of  such  cases. 

The  Pneumonic  Form. — This  form  of  pernicious  malaria  must  be  care- 
fully distinguished  from  pneumonia  which  occurs  as  a  complication  of 
malaria.  To  Baccelli  we  owe  the  demonstration  of  a  class  of  pernicious 
malarial  fevers  which,  in  their  symptomatology,  simulate  lobar  pneumonia. 
The  chief  symptoms  are  cough,  pain  in  the  side,  dyspnoea,  and  the  expectora- 
tion of  blood-stained  sputum.  The  onset  does  not  differ  from  an  ordinary 
paroxysm,  but  sometimes  during  the  attack  the  lung  symptoms  mentioned 
develop  suddenly,  and  the  case  looks  clinically  like  a  case  of  lobar  pneumonia. 
It  will  be  noticed,  however,  that  the  temperature  curve  is  intermittent,  and  that 
during  the  afebrile  periods  the  symptoms  disappear  as  a  rule.  Percussion  shows 
dullness  over  the  affected  lung,  generally  the  lower  lobe  of  one  or  both  lungs, 
and  auscultation  coarse,  sibilant  rales.  The  condition  is  not  a  true  pneumonia, 
but  is  due  to  the  congestion  brought  about  by  the  localization  of  the  plasmodia 
in  the  capillaries  of  the  lungs  and  the  consequent  plugging  of  certain  circulatory 
areas. 


224  THE    PERXICIorS    MALARIAL    FEVERS. 

I  have  observed  several  cases  in  which  the  symptoms  so  closely  simulated 
lobar  pneumonia  that  without  the  microscope  they  would  have  undoubtedly  been 
considered  as  slightly  atypical  instances  of  that  disease.  The  chart  which  is 
here  given  (Chart  C)  is  a  good  illustration  of  the  temperature  in  these  cases,  and 
is  from  a  case  regarded  as  pneumonia,  because  of  the  clinical  symptoms,  until  a 
microscopical  examination  of  the  blood  showed  numerous  tertian  aestivo-autum- 
nal  plasmodia  and  the  administration  of  quinine  quickly  cured  the  infection. 

The  following  case  for  which  I  am  indebted  to  Lt.  Col.  Charles  Richard, 
Medical  Corps,  U.  S.  Army,  is  an  interesting  example  of  this  form  of  malaria. 
"The  patient,  a  soldier,  gave  no  history  of  a  previous  malarial  attack.  He  had 
suffered  for  some  days  from  fever,  but  had  no  chills.  Had  much  pain  in  the 
chest,  a  cough  with  expectoration,  and  some  vomiting.  The  maximum  tem- 
perature was  1040  F.,  but  there  was  no  regularity  in  the  curve.  The  man 
looked  very  sick  and  was  the  picture  of  lobar  pneumonia.  Physical  examina- 
tion showed  a  general  bronchitis.  The  spleen  could  be  felt  below  the  ribs. 
The  examination  of  the  blood  showed  numerous  "ring-forms"  of  the  aestivo- 
autumnal  parasites,  and  treatment  with  quinine  resulted  in  recovery." 

Scheube  has  observed  cases  of  pneumonic  malaria  in  Japan  and  has  no 
hesitation  in  claiming  that  they  are  due  to  the  localization  of  the  plasmodia  in 
the  lungs,  and  if  we  consider  the  frequency  with  which  these  organisms  are  found 
localized  in  other  organs,  as  the  brain,  and  the  connection  clearly  established 
between  such  localization  and  the  symptoms  produced,  we  must  admit  that 
there  is  no  reason  to  doubt  that  the  symptoms  observed  in  this  type  of  ma- 
laria are  due  to  the  plasmodia.  Microscopic  study  of  sections  of  the  lung 
from  fatal  cases  of  malaria  conclusively  prove  that,  in  rare  instances,  the  plas- 
modia occur  in  immense  numbers  in  the  capillaries  of  the  lung,  and  that  the 
lesions  produced  are  sufficient  to  excite  symptoms  simulating  those  of  lobar 
pneumonia. 

The  Bilious  Form  ("Subcontinua  bilosa"). — Certain  cases  of  malarial 
infection  present  a  symptom-complex  in  which  jaundice  and  the  vomiting  of 
bile-stained  fluid  are  most  prominent.  These  cases  have  long  been  known 
under  the  term  of  "bilious  remittent  fever."  The  attack  is  generally  character- 
ized in  the  beginning  by  well-marked  malaria  paroxysms,  but  the  temperature 
soon  becomes  more  or  less  remittent  or  continuous.  Marked  jaundice  ap- 
pears and  severe  vomiting  is  present,  the  matter  vomited  being  greatly  bile- 
stained.  Epistaxis  is  common,  and  hematemesis  often  occurs.  Delirium  may 
be  present  or  there  may  be  a  condition  of  semi-coma  or  even  coma.  The  pa- 
tient often  complains  of  severe  pain  in  the  epigastrium  and  hiccough  is  one 
of  the  most  common  symptoms.  The  temperature  curve  in  well-marked  cases 
is  generally  remittent  or  almost  continuous,  somewhat  resembling  that  of 
typhoid  fever.  If  untreated,  this  form  of  the  disease  is  almost  invariably 
fatal,  but  if  properly  treated  recovery  is  generally  the  result. 

Of  the  very  rare  forms  of  pernicious  malaria  may  be  mentioned  the  syncopal 
form,  first  described  by  Sternberg,  in  which  syncope  occurs  upon  exertion  dur- 


THE    PERNICIOUS    MALARIAL    FEVERS. 


22^ 


15 


226  THE    PERNICIOUS    MALARIAL    FEVERS. 

ing  the  decline  of  the  fever;  the  diaphoretic  form,  characterized  by  the  oc- 
currence of  very  profuse  sweating,  so  severe  as  to  produce  collapse  and  death; 
the  exanthematous  form,  characterized  by  the  occurrence  of  a  scarlatiniform 
rash  upon  the  skin  during  the  paroxysms,  followed  by  desquamation;  the 
pleuritic  form,  in  which  intermittent  attacks  of  sharp,  lancinating  pain  occur  in 
the  side,  and,  lastly,  pernicious  infections  without  fever,  which  have  been  de- 
scribed by  Pampoukis,  who  considers  such  infections  much  more  dangerous 
than  those  in  which  the  temperature  is  high. 

Examination  of  the  Blood  in  Pernicious  Malaria. — The  examination  of 
the  blood  during  an  attack  of  pernicious  malarial  fever  will  almost  invariably 
result  in  the  demonstration  of  large  numbers  of  malarial  plasmodia,  whatever 
species  may  be  concerned  in  the  etiology  of  the  infection.  In  no  other  forms  of 
malaria  are  the  plasmodia  so  numerous  in  the  peripheral  blood  as  in  pernicious 
attacks,  and  often  a  single  microscopic  field  will  contain  from  ten  to  twenty 
infected  corpuscles. 

The  findings  in  the  blood  vary  in  many  cases  with  the  period  of  time  in 
which  the  examination  is  made,  but  as  most  pernicious  infections  are  due  to 
multiple  group  infection,  the  examination  will  show  the  presence  of  plasmodia 
undergoing  various  stages  of  development.  In  the  case  of  regularly  intermittent 
aestivo-autumnal  pernicious  infections,  if  the  blood  be  examined  at  the  acme  of 
the  paroxysm,  the  plasmodia  present  will  be  mostly  of  the  unpigmented  variety, 
wrhile  if  the  blood  be  examined  during  the  intermission  or  one  or  two  hours 
before  the  beginning  of  the  paroxysm,  the  pigmented  forms  of  the  Plasmo- 
dium will  be  found.  At  whatever  time  the  blood  is  examined,  however,  it 
will  be  found  that  the  plasmodia  are  all  approximately  in  the  same  stage  of 
development. 

On  the  other  hand,  if  the  blood  of  cases  suffering  from  pernicious  aestivo- 
autumnal  fever,  in  which  the  temperature  curve  is  irregular  or  almost  con- 
tinuous, be  examined,  it  will  be  found  that  both  pigmented  and  unpigmented 
plasmodia  will  be  present,  at  whatever  period  the  blood  be  examined.  These 
remarks  apply  also  to  pernicious  cases  due  to  the  tertian  and  quartan  plasmodia, 
save  that  in  these  two  forms  of  infection  the  sporulating  stage  will  be  found  in 
peripheral  blood.  As  I  have  shown,  the  presence  of  a  few  organisms  in  the 
peripheral  blood  in  aestivo-autumnal  infections  is  not  always  evidence  of  a 
mild  infection,  as  multitudes  of  plasmodia  may  be  localized  in  the  viscera,  and 
the  infection  may  be  of  a  very  deadly  nature. 

The  aestivo-autumnal  pernicious  fevers  present  themselves  in  so  many 
disguises,  and  exhibit  so  many  atypical  symptoms,  that  even  the  most  acute 
clinical  diagnostician  may  be  entirely  deceived  regarding  these  cases.  The 
microscopical  examination  of  the  blood  should  never  be  neglected  in  the  diag- 
nosis of  any  form  of  malarial  infection,  and  certainly  not  in  pernicious  cases  in 
which  the  life  of  the  patient  is  threatened  and  every  moment  is  precious.  The 
blood  examination  consumes  but  little  time,  is  absolutely  conclusive  in  its  results, 
and  may  save  the  life  of  the  patient.     The  fact  should  never  be  forgotten  that 


THE    PERNICIOUS    MALARIAL    FEVERS.  227 

the  aestivo-autumnal  fevers  may  readily  become  pernicious,  and  that  the  longer 
a  malarial  infection  remains  unrecognized  the  greater  are  the  chances  for  the 
development  of  pernicious  symptoms,  and,  therefore,  the  greater  the  danger  of 
the  patient.  Ignorance  of  the  use  of  the  microscope  is  no  excuse  for  an  omis- 
sion which  may  cost  a  human  life. 

In  illustration  of  this  I  have  in  mind  the  case  of  a  soldier  believed  to  be 
suffering  from  acute  catarrhal  jaundice.  His  symptoms  upon  entering  the 
hospital  were  so  typical  of  this  condition  that  the  physician  in  charge  delayed 
the  request  for  a  blocd  examination  for  several  days.  The  patient  finally 
lapsed  into  a  semi-comatose  condition  and  a  blood  examination  was  then 
requested.  The  blood  was  found  to  be  literally  loaded  with  quotidian  aestivo- 
autumnal  plasmodia,  and,  while  the  most  energetic  treatment  was  at  once  in- 
stituted, despite  all  that  could  be  done  the  patient  died  in  a  few  hours.  Without 
doubt  this  man's  life  could  have  been  saved  had  the  blood  been  examined  earlier, 
before  the  intense  malarial  intoxication  had  occurred.  In  another  case  the 
patient  lay  in  coma  for  three  days  before  a  blood  examination  was  requested, 
upon  the  supposition  that  he  was  suffering  from  some  brain  lesion,  and  here 
again  death  occurred  because  the  malarial  condition  was  not  determined  in 
time.  The  only  safety  against  mistakes  of  this  character  in  regions  in  which 
malaria  is  endemic  or  in  the  case  of  patients  coming  from  malarial  localities  is 
a  careful  microscopical  examination  of  the  blood. 


CHAPTER  IV. 

Latent    Malaria;    Masked    Malaria;    Recurrent    Malaria;    Etiology    of    Latency 
and  Recurrence;  Intracorpuscular  Conjugation  of  the   Malarial  Plasmodia. 

Latent  Malarial  Infection. — In  the  study  of  the  malarial  fevers  one  is 
much  impressed  by  the  fact  that  a  considerable  proportion  of  patients  showing 
some  form  of  the  plasmodia  in  the  blood  present  no  symptoms  of  the  infection, 
and  these  cases  are  of  great  importance  from  an  epidemiological  standpoint. 
In  such  patients  the  infection  is  latent,  a  latent  malarial  infection  being  one  in 
which  the  plasmodia  may  be  demonstrated  to  be  present  in  the  blood,  but  in 
which  no  clinical  symptoms  of  the  disease  of  sufficient  gravity  to  attract  atten- 
tion are  to  be  observed.  The  term  should  not  be  confined  to  those  instances  in 
which  no  symptoms  of  malaria  have  ever  been  present,  for  if  the  plasmodia  be 
present  in  the  blood  during  the  afebrile  period  in  recurrent  cases,  the  disease  is 
as  truly  latent  during  that  period  as  before  the  initial  attack.  In  many  latent 
infections  some  complicating  disease  may  be  present,  and  this  is  almost  invari- 
ably true  of  latent  malarial  infections  discovered  in  hospital  practice.  It  is 
obvious  that  all  cases  of  latent  malarial  infection  are  a  great  source  of  danger  to 
others  in  localities  where  the  Anophelinae  are  present. 

The  material  upon  which  the  observations  and  conclusions  detailed  in 
this  chapter  are  based  consists  of  1,653  cases  of  malarial  infection,  1,267  °f 
which  were  observed  at  the  U.  S.  Army  General  Hospital,  Presidio,  of  San 
Francisco,  in  American  soldiers  returning  from  service  in  the  Philippine  Islands, 
and  386  cases  studied  at  Camp  Stotsenburg,  in  the  Philippine  Islands.  Of  the 
latter  cases  248  occurred  in  Americans  and  138  in  Filipinos.  Besides  the  cases 
mentioned  a  considerable  portion  of  the  data  regarding  latency  and  recurrence 
has  been  obtained  from  the  observation  of  malarial  infections  contracted  by 
American  soldiers  while  in  Cuba,  and  studied  at  the  Simpson  U.  S.  Army  General 
Hospital,  Fortress  Monroe,  and  at  Camp  Columbia,  near  Havana,  Cuba. 
Of  the  1,653  cases  of  malaria  upon  which  the  statistics  of  this  chapter  are  based, 
424,  or  a  little  over  25  per  cent.,  were  latent  infections.  Of  these  307  were  in 
American  soldiers,  while  115  occurred  in  natives  of  the  Philippine  Islands. 

As  regards  the  species  of  plasmodium  present  in  the  blood,  the  424  cases 
were  divided  as  follows: 

Tertian,  no 

Quartan,  8 

Tertian  aestivo-autumnal,  272 

Quotidian  aestivo-autumnal,  25 

Combined  tertian  and  tertian  aestivo-autumnal,      7 
Combined  tertian  and  quotidian  aestivo-autum- 
nal, 2 

424 
228 


LATENT,  MASKED  AND  RECURRENT  MALARIAL  FEVERS.      22C) 

In  order  to  understand  the  significance  of  the  above  table  it  will  be  neces- 
sary to  consider  the  latent  infections  of  Americans  and  of  natives  of  the  Philip- 
pines separately. 

Latent  Infections  in  Americans. — The  latent  infections  of  Americans,  as 
regards  the  species  of  plasmodium  present,  were  divided  as  follows: 

Tertian,  81 

Quartan,  o 

Tertian  aestivo-autumnal,  199 

Quotidian  aestivo-autumnal,  21 

Combined  tertian  and  tertian  aestivo-autumnal,     4 
Combined  tertian  and  quotidian  aestivo-autum- 
nal, 2 

3°7 

The  307  latent  cases  observed  in  Americans  occurred,  with  but  few  ex- 
ceptions, in  soldiers  invalided  home  from  the  Philippines.  As  is  evident,  the 
aestivo-autumnal  plasmodia  are  much  more  frequently  encountered  in  latent 
cases  than  any  other  species,  220  of  the  307  latent  infections  in  Americans  being 
due  to  either  the  tertian  or  quotidian  aestivo-autumnal  plasmodium.  The 
occurrence  of  so  large  a  proportion  of  aestivo-autumnal  infections  is  not  due  to 
any  peculiarity  in  the  type  of  plasmodia  other  than  that  the  aestivo-autumnal 
organisms  are  much  more  resistant  to  quinine  than  the  other  species,  and  for 
that  reason  more  latent  infections  with  these  plasmodia  are  found  in  the  class  of 
patients  examined,  who  had  probably  all  taken  quinine  at  one  time  or  another. 
It  is  also  true  that  in  the  Philippines,  as  in  other  tropical  countries,  the  aestivo- 
autumnal  fevers  are  more  prevalent  than  tertian  or  quartan  fevers. 

The  fact  that  aestivo-autumnal  infections  are  particularly  apt  to  exist  in  a 
latent  form  is  of  importance,  as  the  diagnosis  of  such  an  infection  may  prevent  a 
sudden  pernicious  attack;  and  it  is  also  important  from  an  epidemiological 
standpoint,  as  an  individual  thus  harboring  the  plasmodia  is,  or  may  become,  a 
source  of  infection  to  the  community  in  which  he  is  living.  It  is  thus  evident 
that  the  blood  of  every  individual  returning  from  a  malarial  region  should  be 
examined,  both  as  a  safeguard  to  himself  and  to  the  community  in  which  he  may 
be  residing. 

Frequency  of  Latent  Infection  in  Americans. — Of  the  1,297  cases  of 
malaria  studied  in  Americans,  307  or  nearly  24  per  cent.,  were  latent  infections. 
It  should  be  remembered  that  in  all  of  these  cases  there  were  absolutely  no 
symptoms  of  malaria  present,  and  had  it  not  been  for  the  examination  of  the 
blood  these  men  might  have  remained  sources  of  infection  for  weeks  or  months. 

As  showing  the  frequency  of  latent  malarial  infections  and  the  importance 
of  their  recognition,  I  quote  the  following  from  a  report  upon  latent  and  masked 
infections  by  the  writer,  published  in  American  Medicine,  in  1904: 

In  August,  1902,  Company  H,  16th  Infantry,  U.  S.  Army,  returned  to  San 
Francisco  from  the  Philippines,  having  served  in  the  Cagayan  Valley,  a  notori- 


23O  LATENT,    MASKED    AND    RECURRENT    MALARIAL    FEVERS. 

ously  malarial  region  in  those  islands.  On  August  16,  1902,  this  company,  out 
of  a  total  strength  of  some  60  men,  had  14  men  in  hospital  suffering  from  mala- 
rial infection,  all  having  had  chills  since  arrival  in  the  United  States.  On  ac- 
count of  this  large  proportion  of  infected  men,  I  believed  that  it  would  be 
advisable  to  make  a  blood  examination  of  the  entire  company,  and  accordingly, 
on  August  17,  I  examined  the  blood  of  every  man  on  duty  in  Company  H,  with 
the  following  results:  Of  the  47  men  who  were  doing  duty,  including  the  officers, 
I  found  that  27  presented  some  form  of  malarial  parasite  in  their  blood.  Of 
these  27  cases,  25  were  infected  with  the  aestivo-autumnal  plasmodia;  13  show- 
ing gametes  (crescents)  of  the  tertian  aestivo-autumnal  species;  10  showing 
crescents  and  ring-forms  of  the  same  species;  two  showing  crescents  and  ring- 
forms  of  the  quotidian  aestivo-autumnal  plasmodium;  and  two  showing  nearly 
full-grown  forms  of  the  simple  tertian  plasmodium.  Thus  of  a  total  strength  of 
60  men,  41,  which  includes  those  sick  in  hospital,  showed  some  form  of  malaria 
infection,  while  27,  without  presenting  any  symptoms  of  malaria,  showed 
parasites  in  the  blood. 

A  study  of  the  blood  findings  in  this  company  is  of  great  significance,  not 
only  as  showing  the  importance  of  a  blood  examination  in  persons  returning 
from  the  tropics,  but  because,  in  most  instances,  the  gametes  of  the  aestivo- 
autumnal  plasmodia,  the  most  dangerous  of  the  malarial  parasites,  are  the 
forms  present.  As  the  gametes,  or  crescents,  are  the  forms  which  undergo 
development  within  the  mosquito  it  is  evident  that  these  men  could  infect 
mosquitoes  of  the  genus  Anopheles  wherever  they  might  go.  In  this  way 
localities  hitherto  free  from  this  dreaded  type  of  malaria  might  become  infected. 

Latent  Malarial  Infection  Complicating  Other  Diseases. — A  very 
large  number  of  latent  malarial  infections  in  Americans  occur  as  complications 
of  some  other  disease  process,  and  it  is  important  that  the  malarial  factor  in 
such  cases  be  recognized  and  removed.  As  an  illustration  of  the  frequency  of 
this  condition  I  have  compiled  the  following  table,  giving  the  original  diagnosis 
in  106  cases  in  which  a  latent  malarial  infection  was  found  to  exist.  In  nearly 
all  of  these  cases  the  removal  of  the  malarial  complication  resulted  in  improve- 
ment of  the  health  of  the  patient. 


Diagonisis 


Number  of  cases 


Chronic  dysentery    

Chronic  diarrhoea     

Pulmonary  tuberculosis     

Fractures  and  wounds 

Chronic  gastritis     

Amoebic  dysentery     

Chronic  indigestion    

Hernia      

Otitis  media       I  3 


15 

20 

3 

1 1 
8 

JS 
3 
3 


LATENT,    MASKED   AND    RECURRENT    MALARIAL    FEVERS. 


23I 


Diagnosis 


Number  of  cases 


Acute  melancholia      

Rheumatism      

Syphilis    

Insanity     

Paralysis    

Acute  dementia    

Convalescent  from  operation 

Arthritis  formans      

Retinitis     

Varicocele 

Tachycardia    

Uncinariasis    

Diabetes  mellitus   

Paraplegia    

Acute  endocarditis 

Hemorrhoids 

Adenitis,  cervical    


to6 


A  consideration  of  some  of  the  data  given  in  the  above  table  is  of  interest. 

In  15  cases  of  chronic  dysentery,  non-amoebic  in  type,  a  latent  malarial 
infection  was  discovered.  All  of  these  patients  gave  a  history  of  having  suffered 
from  malaria  in  the  Philippines,  but  of  not  having  had  any  symptoms  of  the 
disease  since  arrival  in  the  United  States.  The  much  controverted  statement 
that  there  exists  a  form  of  dysentery  due  to  the  localization  of  the  malarial 
plasmodia  in  the  capillaries  of  the  intestine  is  of  interest  in  connection  with  these 
cases,  as  treatment  of  the  malarial  infection  resulted  in  every  case  in  marked 
improvement  of  the  dysenteric  condition  and  ultimately  in  complete  recovery,  so 
that  it  is  probable  that  some  of  these  cases  were  entirely  malarial  in  character. 
From  personal  observation  I  know  that  some  aestivo-autumnal  infections  are 
accompanied  by  a  bloody  diarrhoea,  and  it  is  my  belief  that  many  cases  diag- 
nosed as  dysentery  in  tropical  countries  are  due  to  the  invasion  of  the  intestines 
by  the  malarial  plasmodia  or  to  the  action  of  the  malarial  poison.  The  same 
remarks  apply  to  the  20  cases  of  chronic  diarrhoea  in  which  a  latent  malarial 
infection  was  discovered. 

In  15  cases  of  amoebic  dysentery  a  latent  malarial  infection  was  observed. 
In  these  cases  Entamoeba  histolytica  was  present  in  the  faeces  and  one  of  the 
species  of  plasmodia  in  the  blood. 

In  nine  cases  of  fractures  and  two  of  bolo  wounds  an  examination  of  the 
blood  showed  the  presence  of  malarial  plasmodia,  although  no  symptoms  of 
such  infection  were  noticed.  This  was  also  true  in  one  case  convalescent  from 
operation. 


232      LATENT,  MASKED  AND  RECURRENT  MALARIAL  FEVERS. 

Latent  Infection  in  Natives  of  the  Philippine  Islands. — I  have  already 
noted  the  results  of  various  observers  in  the  examination  of  the  blood  of  native 
races  in  tropical  countries,  and  have  shown  that  latent  infection  is  very  common 
in  certain  localities  among  the  native  population.  The  following  observations 
upon  the  latent  infections  of  the  natives  of  the  Philippines,  made  at  Camp 
Stotsenburg,  are  in  agreement  with  those  of  other  observers  and  prove  that  the 
Filipino,  like  other  tropical  races,  suffers  from  malarial  infections  in  early 
childhood,  but,  unlike  some  native  races,  does  not  establish  any  marked  im- 
munity in  adult  life. 

Frequency  of  Latent  Infection  in  Filipinos. — During  five  months  in 
which  I  was  stationed  at  Camp  Stotsenburg  I  observed  386  cases  of  malaria  in 
which  I  was  able  to  demonstrate  the  parasites  in  the  peripheral  blood.  Of 
these,  248  occurred  in  Americans  and  138  in  Filipinos.  As  regards  the  type  of 
infection,  98  were  infected  with  the  tertian  plasmodium,  of  which  63  were 
Americans  and  35  natives;  eight  with  the  quartan  plasmodium,  of  which  2  were 
Americans  and  6  natives;  and  272  with  the  aestivo-autumnal  plasmodia, 
183  being  Americans  and  89  natives.  Of  the  aestivo-autumnal  infections, 
258  were  due  to  the  tertian  aestivo-autumnal  plasmodium  and  14  to  the 
quotidian  variety.  All  of  the  latent  infections,  115  in  number,  occurred  in 
Filipinos. 

It  appeared  probable  to  me  in  considering  the  malarial  situation  at  this 
post  that  the  natives  living  in  the  barrios  in  close  proximity  were  the  principal 
source  of  infection,  as  the  sanitary  conditions  in  the  post  proper  were  such  as  to 
prohibit  the  belief  that  much  malarial  infection  could  originate  there,  while 
breeding-places  of  mosquitoes  abounded  in  the  barrios  and  mosquitoes  belong- 
ing to  the  Anophelinae  were  much  more  numerous  in  them  than  at  the  post. 
The  barrios  were  constantly  visited  by  the  soldiers,  especially  at  night,- and  the 
conditions  for  the  spread  of  both  human  and  mosquito  infection  were  ideal.  In 
order  to  determine  how  large  a  proportion  of  the  native  population  of  the  bar- 
rios was  infected,  I  made  blood  examinations  of  as  many  natives  as  possible, 
living  within  two  miles  of  the  post.  The  result  proved  beyond  question  that 
the  origin  of  malarial  infection  at  Camp  Stotsenburg  was  to  be  found  very 
largely  in  the  natives  living  in  the  immediate  vicinity,  and  that  any  efforts  to 
limit  the  spread  of  the  disease  must  take  this  condition  into  account.  In  a  con- 
siderable number  of  the  cases  of  latent  infection,  even  in  the  youngest  children, 
a  history  of  previous  attacks  of  fever  could  be  obtained,  but  in  none  of  them 
were  any  symptoms  of  malaria  present  at  the  time  of  the  examination  of  the 
blood.  In  all,  the  blood  of  225  Filipinos  was  examined,  of  which  115,  or  51.1 
per  cent.,  showed  a  latent  malarial  infection. 

This  percentage  of  latent  malarial  infection  should  not  be  regarded  as 
typical  of  all  localities  in  the  Philippines,  for  many  localities  are  free  from 
malaria,  while  in  others  the  malarial  index  is  low.  Routine  blocd  examina- 
tions of  the  natives  of  a  tropical  country  will  give  much  valuable  information  as 
to  the  malarial  endemicity  of  the  locality,  and  such  examinations  should  be 


LATENT,  MASKED  AND  RECURRENT  MALARIAL  FEVERS.      233 

made  before  permanent  military  posts  or  civilian  residences  are  established  in 
the  tropics. 

Of  the  115  latent  infections  discovered,  the  tertian  plasmodium  was 
present  in  29,  the  quartan  in  six,  and  the  aestivo-autumnal  in  77;  of  the  latter, 
73  were  due  to  the  tertian  aestivo-autumnal  plasmodium,  and  four  to  the 
quotidian  aestivo-autumnal  plasmodium.  There  were  three  combined  infec- 
tions with  the  tertian  and  the  tertian  aestivo-autumnal  plasmodia. 

Latent  Infection  in  the  Adult  Natives. — I  was  able  to  examine  the  blood 
of  but  45  adults,  of  whom  28,  or  62.2  per  cent,  were  infected;  of  these,  five 
infections  were  due  to  the  tertian  plasmodium,  and  23  to  the  tertian  aestivo- 
autumnal  plasmodium.  It  is  very  probable  that  a  further  study  of  the  blood  of 
a  greater  number  of  adults  would  materially  reduce  this  great  percentage  of 
infections,  but  from  the  results  obtained,  it  is  evident  that  the  adult  Filipino  is 
more  often  infected  than  the  negro  in  Africa  or  the  native  of  India.  It  is  more 
than  probable  that  the  adult  Filipino  possesses  little  or  no  immunity  to  malaria, 
despite  the  fact  that  in  malarial  localities  such  adults  have,  from  childhood, 
suffered  from  repeated  attacks  of  the  disease.  I  have  notes  upon  several  adults, 
who,  within  two  years,  were  admitted  to  the  hospital  from  8  to  16  times  with 
malarial  infections.  The  reason  for  this  lack  of  immunity  of  the  adult  Filipino 
to  malarial  infection  is  difficult  to  understand,  but  I  believe  that  there  is  no 
question  but  that  it  does  exist  to  a  marked  degree  even  in  the  most  malarial 
localities. 

Latent  Infection  in  Native  Children. — Of  the  180  children  whose  blood 
I  examined,  87  or  48.3  per  cent.,  showed  the  presence  of  the  malarial  plasmodia. 
Of  these  latent  infections,  34  were  due  to  the  tertian  plasmodium,  six  to  the 
quartan,  and  44  to  the  aestivo-autumnal  species.  Of  the  latter,  40  were  due  to 
the  tertian  aestivo-autumnal  species  and  four  to  the  quotidian.  There  were 
three  combined  infections  with  the  tertian  and  tertian  aestivo-autumnal  plasmo- 
dia. The  infections  in  children  diminished  in  number  with  advancing  age. 
Thus,  between  the  ages  of  one  month  and  five  years,  among  40  children,  79  per 
cent,  were  infected;  between  5  and  10  years,  37  per  cent.;  and  between  10  and  15 
years,  24.5  per  cent.  These  results  agree  with  those  of  Koch,  Stephens  and 
Christophers,  James,  and  others,  who  invariably  found  that  the  younger  the 
child,  the  more  susceptible  it  was  to  malaria. 

The  percentage  of  latent  infections  in  children  varies  considerably  in  the 
different  barrios  in  which  the  examinations  were  made.  For  instance,  in  the 
town  of  Mabalacat,  25  school  children  between  the  ages  of  5  and  10  years  were 
examined,  of  whom  seven,  or  28  per  cent.,  were  found  infected;  while  of  children 
between  10  and  15  years  of  age,  35  were  examined;  of  whom  seven,  or  20  per 
cent.,  were  infected.  In  the  town  of  Dolores,  11  school  children  between  the 
ages  of  5  and  10  years  were  examined,  of  whom  seven,  or  63.6  per  cent.,  wrere 
infected;  while  of  13  children  between  10  and  15  years  of  age,  four,  or  nearly  31 
per  cent.,  were  infected. 

Family  Infection. — Not  only  do  the  barrios  differ  in  the  ratio  of  malarial 


234 


LATENT.  MASKED  AND  RECURRENT  MALARIAL  FEVERS. 


individuals  to  those  in  health,  but  certain  portions  of  the  barrios  are  most  ma- 
larious, while  other  portions  are  almost  free  from  infection.  It  was  also 
observed  that  malaria  in  these  barrios  was  very  largely  a  family  disease, 
certain  families  suffering  severely,  while  others  were  free  from  infection.  The 
following  table  illustrates  the  family  character  of  malarial  infection,  being 
compiled  from  the  data  obtained  in  one  barrio  where  all  of  the  families  resided. 


Family 

No.  members 

No.  infected 

Type  of  infection 

i 

4 

2 

i  aes-autumn.     i  ter. 

2 

3 

2 

2  aes-autumn. 

3 

4 

2 

i  aes-autumn.      i  ter. 

4 

5 

4 

2  aes-autumn.      i  ter. 
i  quartan. 

5 

4 

2 

2  aes-autumn. 

6 

3 

2 

2  aes-autumn. 

7 

4 

3 

2  aes-autumn.      i  ter. 

8 

3 

2 

i  aes-autumn.      i  ter. 

9 

3 

2 

2  tertian. 

IO 

6 

4 

2  aes-autumn.      2  ter. 

In  considering  this  table  it  should  be  remembered  that  all  these  infections 
were  latent  in  character,  and  I  have  repeatedly  observed  families  in  which  every 
member  was  suffering  from  a  malarial  infection,  either  latent  or  active.  Family 
No.  4  in  the  above  table  is  of  special  interest  because,  of  its  five  members,  one 
was  suffering  from  a  severe  attack  of  tertian  malaria  at  the  time  I  made  the  ex- 
amination, while  of  the  other  four,  two  presented  aestivo-autumnal,  one  the 
quartan,  and  the  other  the  tertian  plasmodium  in  the  blood,  so  that  in  this  one 
family  all  the  species  of  the  malarial  plasmodium  couldbe  studied. 

The  pathology  of  latent  malarial  infection  has  already  been  considered  in 
the  chapter  devoted  to  the  special  pathology  of  the  malarial  infections. 

Practical  Deductions.  —  From  the  facts  given  above,  I  believe  that 
it  is  obvious  that  latent  malarial  infections  are  of  much  importance  from 
both  epidemiological  and  clinical  standpoints;  it  is  certainly  true  that  latent 
infections  are  a  great  source  of  malarial  disease,  and  in  the  tropics,  the  latent 
infection  of  the  native  is  undoubtedly  the  principal  source  of  infection  of  the 
white  man.  The  importance  of  an  examination  of  the  blood  of  the  native 
population  of  any  given  locality  cannot  be  overestimated  in  the  fight  against 
malaria.  This  is  especially  true  in  the  tropics,  for  only  from  the  results  of  such 
an  examination  can  the  endemic  areas  of  malaria  be  found  and  guarded  against. 
Only  to  one  who  has  attempted  it,  can  the  almost  hopeless  task  of  exterminating 
mosquitoes  in  tropical  regions  be  appreciated,  and,  in  fact,  in  many  localities  it 
is  impossible  of  accomplishment.     This  being  so,  it  is  apparent  that  it  is  useless 


LATENT,  MASKED  AND  RECURRENT  MALARIAL  FEVERS. 


!35 


to  rid  a  locality  of  malaria,  if  it  is  impossible  to  eliminate  the  mosquito,  unless 
the  infection  is  first  stopped  in  the  native,  and  in  the  tropics  it  appears  to  me 
that  the  greatest  hope  of  success  is  combating  malaria  lies  in  the  treatment  of 
the  latent  infections  of  the  natives. 

Masked  Malarial  Fever.— Cases  of  malarial  infection  in  which  the 
symptoms  are  masked  by  those  of  some  other  disease  or  in  which  the  symptoms 
closely  resemble  those  of  other  diseases  are  known  as  masked  infections.  In 
such  cases  malarial  symptoms  are  present,  but  they  are  overshadowed  by  the 
symptoms  of  the  complicating  disease.  Such  cases  are  common  and  should 
be  carefully  distinguished  from  those  instances  of  latent  infection  occurring 
during  other  disease  processes.  In  the  latent  cases  no  symptoms  of  malaria 
are  present,  while  symptoms  are  present  in  the  masked  cases.  The  following 
table  shows  the  diagnosis  in  91  cases  of  masked  malaria  in  all  of  which  the 
symptoms  of  the  disease  diagnosed  masked  those  of  the  malarial  infection. 


Disease 


No.  cases  masked 


Chronic  dysentery    .  .  .  . 

Chronic  diarrhoea 

Pulmonary  tuberculosis 
Amoebic  dysentery  .  .  .  . 

Acute  bronchitis 

Rheumatism 

Measles 

Typhoid  fever 

Pneumonia    

Abscess  of  the  liver  .... 

Furunculosis 

Diabetes  mellitus 

Gonorrhoea    

Cellulitis     

Appendicitis    


45 

5 


9* 


The  instances  in  which  the  malarial  symptoms  so  closely  simulate  those 
of  some  other  disease  are  also  numerous,  and  it  may  truly  be  said  that  malaria 
may  simulate  almost  any  disease  so  closely  that  only  a  microscopical  examina- 
tion of  the  blood  will  enable  us  to  make  a  diagnosis.  As  a  rule,  however,  the 
periodical  nature  of  the  attacks  will  raise  a  suspicion  of  their  malarial  nature. 
It  should  also  be  remembered  that  in  the  older  literature  of  malaria  many 
conditions  were  classed  under  masked  malaria  which  were  not  malarial  in 
nature  and  which  would  have  been  correctly  diagnosed  had  the  plasmodia  been 
discovered  at  the  time  they  were  described.  No  case  should  be  considered  as 
one  of  masked  malaria,  unless  a  blood  examination  has  shown  the  presence  of 


236 


LATENT,  MASKED  AND  RECURRENT  MALARIAL  FEVERS, 


the  malarial  plasmodium.  Among  the  most  common  atypical  symptoms  of 
malaria  which  are  often  considered  as  being  due  to  some  other  disease  may  be 
mentioned  various  neuralgic  affections,  periodical  in  type,  especially  of  the 
fifth  nerve,  the  intercostal  nerves,  and  of  the  occipital  region;  convulsions 
especially  common  in  malarial  attacks  in  children;  various  nervous  conditions, 
as  insomnia,  delirium,  melancholia,  mania,  and  dizziness;  and  certain  of  the 
infectious  diseases,  may  be  so  closely  simulated  by  malaria  as  to  be  almost 
indistinguishable,  especially  typhoid,  pneumonia,  yellow  fever,  cerebrospinal 
meningitis,  and  pulmonary  tuberculosis. 

The  following  table  of  96  cases  of  masked  malaria  in  which  the  diagnosis 
as  made  before  the  malarial  nature  of  the  condition  was  discovered  is  given,  well 
illustrates  how  frequently  malaria  simulates  other  disease  processes,  and 
how  valuable  a  microscopical  examination  of  the  blood  is  in  the  diagnosis  of 
disease.  In  all  of  these  cases,  the  symptoms  present  were  sufficiently  typical 
of  the  disease  diagnosed  as  to  render  the  diagnosis  justifiable,  and  in  all,  treat- 
ment with  quinine  caused  a  rapid  disappearance  of  the  symptoms. 


Diagnosis 


No.  of  cases 


Neuralgia,  facial 

Chronic  dysentery    

Chronic  diarrhoea 

Pulmonary  tuberculosis  . 

Acute  bronchitis 

Pneumonia,  lobar      

Appendicitis    

Peritonitis 

Insolation    

Syphilis    

Melancholia 

Insanity 

Rheumatism,  muscular   . 

Typhoid  fever 

Malta  fever 

Anaemia     

Acute  catarrhal  jaundice 

Yellow  fever 

Cerebrospinal  meningitis 


3 

15 

6 

5 
4 
3 


4 
2 

4 
10 

6 
20 


96 


It  is  not  necessary  to  consider  this  table  in  detail,  but  I  would  call  attention 
to  the  fact  that  in  most  of  these  cases  the  infection  was  due  to  the  aestivo-autum- 
nal  plasmodium,  and  that  most  of  them  had  been  insufficiently  treated  with 
quinine,  which,  no  doubt,  had  much  to  do  with  the  atypical  nature  of  the 
symptoms.     The  confusion  of  malarial  infection  with  typhoid,  Malta  fever, 


LATENT,    MASKED    AND    RECURRENT    MALARIAL    FEVERS.  237 

and  tuberculosis  is  of  frequent  occurrence  and  has  much  to  justify  it,  as  the 
symptoms  of  malarial  fever  of  aestivo-autumnal  type,  often  very  closely  simulated 
those  of  any  one  of  these  diseases. 

At  first  sight  it  would  seem  almost  impossible  that  a  diagnosis  of  lobar 
pneumonia  would  be  made  in  a  case  of  malarial  fever.  I  have  already  described 
the  occurrence  of  cases  of  malaria  so  closely  simulating  lobar  pneumonia  that 
without  the  microscope  a  differential  diagnosis  could  not  be  made,  and  believe 
that  the  two  following  clinical  histories  amply  illustrate  how  closely  the  symp- 
toms of  a  malarial  infection  may  simulate  those  of  lobar  pneumonia. 

I  am  indebted  for  the  notes  of  Case  I  to  Dr.  Edmund  Barry,  formerly  of 
the  United  States  Army. 

Case  I. — W.  D.  C.  Patient  was  admitted  to  the  hospital  from  the  Presidio 
of  San  Francisco,  with  a  transfer  slip  diagnosis  of  lobar  pneumonia.  On  admis- 
sion the  patient  was  somewhat  emaciated;  his  mental  condition  was  apathetic; 
tongue  coated,  and  bowels  constipated;  he  complained  of  chilliness  most  of  the 
time.  The.  spleen  was  enlarged  considerably  and  tender.  Soon  after  admission 
he  had  a  severe  chill  and  became  delirious,  his  temperature  reaching  106. 2°  F. 
There  was  marked  difficulty  in  breathing  and  severe  pain  in  the  side.  An  ex- 
amination of  the  lungs  showed  marked  friction  sounds  over  the  middle  lobe  of 
the  right  lung,  and  dullness  over  the  same  area.  Patient  remained  slightly 
delirious  for  five  days  and  during  this  time  the  physical  signs  of  pneumonia 
increased,  marked  dullness  developing  over  the  lower  lobe.  Respirations 
were  rapid,  exceeding  50,  and  the  pulse  very  weak.  He  coughed  considerably, 
but  there  was  no  expectoration.  At  the  end  of  five  days  the  blood  was  examined 
and  numerous  "ring  forms"  of  the  tertian  aestivo-autumnal  plasmodium  were 
found.  Immediately  upon  receipt  of  the  laboratory  report,  quinine  was  admin- 
istered, and  in  two  days  the  patient  was  so  much  better  that  he  was  able  to  sit  up 
and  was  about  within  four  days. 

I  personally  examined  this  patient  during  the  period  in  which  he  was 
considered  to  be  suffering  from  pneumonia,  and  his  symptoms  were  typical 
of  that  disease.  His  temperature  curve  was  atypical,  however,  showing  marked 
remissions.  (See  Chart  C.) 

Case  II. — C.  S.  The  patient  was  admitted  to  the  hospital  with  a  diagnosis 
of  acute  lobar  pneumonia  of  the  lower  lobe,  right  lung,  and  at  the  time  of  admis- 
sion was  in  a  comatose  state.  After  recovery  the  following  history  was  obtained: 
The  illness  began  with  a  soreness  in  the  chest  and  expectoration,  slightly  blood- 
tinged.  Just  before  admission  he  had  a  severe  chill,  accompanied  by  pain  in 
both  sides  of  the  chest,  and  at  this  time  he  spat  up  considerable  blood.  The 
pain  was  very  distressing  on  deep  inspiration.  At  the  time  of  admission  his 
respirations  were  40;  pulse  100;  and  temperature  1040  F. 

An  examination  of  his  lungs  showed  increased  vesicular  breathing,  almost 
bronchial  in  character;  increased  vocal  fremitus;  and  numerous  crepitant  rales 
over  the  right  lung  and  lower  lobe  of  the  left.  Both  lower  lobes  were  dull  upon 
percussion.  The  spleen  was  very  much  enlarged  and  there  was  slight  enlarge- 
ment of  the  liver.  He  was  admitted  to  hospital  Jan.  20,  and  a  blood  examination 
was  made  the  next  day.      The  blood  showed  numerous  full-grown  tertian  plas- 


238      LATENT,  MASKED  AND  RECURRENT  MALARIAL  FEVERS. 

modia  and  a  few  "ring-forms"  of  the  quotidian  aestivo-autumnal  plasmodium. 
Before  the  blood  examination  was  made  the  diagnosis  of  pneumonia  was  con- 
curred in  by  the  attending  surgeon,  and  treatment  for  that  condition  insti- 
tuted. On  receipt  of  the  report  from  the  laboratory,  quinine  was  administered, 
which  was  followed  by  a  rapid  improvement  in  the  patient's  condition,  the  tem- 
perature falling  from  1040  F.  to  960  F.  The  administration  of  quinine  was  con- 
tinued and  rapid  recovery  ensued. 

In  this  case  we  have  a  clear  history  of  the  outset  of  what  was  apparently 
true  lobar  pneumonia,  the  symptoms  agreeing  in  every  way  with  those  usually 
observed  in  that  disease.  There  was  pain  in  the  side,  chill,  high  temperature 
expectoration  of  blood-stained  sputum,  and  the  physical  signs  which  are 
considered  so  characteristic  of  lobar  pneumonia,  yet  two  days'  treatment  with 
quinine  brought  the  temperature  to  normal,  all  of  the  symptoms  disappeared, 
and  the  patient  was  up  and  about  within  a  week.  Such  cases  as  these  prove 
that  the  localization  of  the  malarial  plasmodia  within  the  capillaries  of  the 
lungs  is  capable  of  producing  true  pneumonic  symptoms. 

In  rare  instances  a  malarial  infection  will  simulate  appendicitis  or  peri- 
tonitis so  closely  as  to  render  the  diagnosis  impossible  clinically.  The  following 
case  is  of  special  interest,  as  it  demonstrated  how  closely  malarial  infection  may 
simulate  appendicitis. 

The  patient  was  an  officer  of  the  U.  S.  Army  who  was  transferred  to  the 
Army  General  Hospital  at  San  Francisco  with  a  diagnosis  of  suspected  appen- 
dicitis, transfer  being  made  with  a  view  to  operation  if  the  diagnosis  was  verified. 
He  gave  a  history  of  having  had  intermittent  malarial  attacks  in  the  Philippines 
which  did  not  necessitate  admission  to  sick  report.  He  had  not  been  feeling 
well  for  some  time,  and  on  the  day  before  admission  to  the  hospital  he  had.  an 
attack  of  pain  in  the  region  of  the  ascending  colon.  Upon  admission  he  com- 
plained of  pain  in  this  region,  at  times  very  severe ;  his  tongue  was  coated ; 
bowels  regular;  and  his  pulse  and  temperature  about  normal.  A  blood  count 
was  made  and  a  slight  leucocytosis  was  found.  Physical  examination  showed 
no  rigidity  of  the  muscular  wall,  but  he  complained  of  pain  in  the  right  iliac 
region  on  pressure,  and  after  careful  examination,  operation  the  next  morning 
was  determined  upon.  That  evening  he  had  a  slight  chill  and  his  temperature 
rose  to  1040  F.  An  examination  of  the  blood  was  made  and  numerous  hyaline 
forms  of  the  tertian  aestivo-autumnal  plasmodium  were  found.  Quinine  was 
promptly  administered,  which  resulted  at  once  in  a  fall  of  temperature,  and 
continued  administrations  in  complete  recovery.  In  this  case  an  operation 
would  undoubtedly  have  been  performed  in  the  morning  for  a  condition  essen- 
tially malarial  in  character. 

It  is  obvious  that  the  recognition  of  these  cases  of  latent  and  masked  malarial 
fever  is  of  the  greatest  importance,  as  in  the  latent  infections  we  are  thus  able 
to  cure  the  disease  before  any  annoying  or  dangerous  symptoms  appear,  and 
in  the  masked  cases  we  are  able  to  remove  the  malarial  element  in  those  cases 
in  which  other  disease  symptoms  mask  the  malaria,  or  discover  and  treat  the 


LATENT,  MASKED  AND  RECURRENT  MALARIAL  FEVERS.      239 

true  cause  of  disease  in  those  cases  in  which  the  malarial  symptoms  resemble 
those  of  other  infections. 

Duration  of  Latent  and  Masked  Malarial  Infections. — The  length  of 
time  during  which  a  latent  infection  may  exist  is  uncertain,  but  it  is  probable 
that  in  many  cases  it  may  be  for  weeks  or  months.  I  recall  one  case  in  which 
the  aestivo-autumnal  plasmodia  were  found  in  the  blood  for  six  weeks  before 
a  paroxysm  occurred,  and  I  have  observed  many  cases  in  which  the  plasmodia 
were  demonstrated  in  the  blood  for  from  seven  to  fourteen  days  before  the 
appearance  of  clinical  symptoms. 

The  masked  cases  may  continue  for  weeks  where  the  infection  is  not  of 
a  pernicious  character  or  death  may  occur  within  a  few  days. 

It  should  always  be  borne  in  mind  that  most  latent  and  masked  infections 
are  caused  by  the  aestivo-autumnal  plasmodia  and  that  such  infections  are 
especially  liable  to  develop  pernicious  symptoms;  that  the  clinical  symptoms 
in  many  of  these  cases  are  absolutely  unreliable,  so  far  as  diagnosis  goes;  and 
that  in  all  diseases  occurring  in  malarial  regions  a  microscopical  examination 
of  the  blood  should  never  be  omitted. 


Recurrent  Malarial  Infections. 

It  is  probably  a  fact  that  with  very  few  exceptions  (and  these  most  vigorously 
treated  with  quinine)  every  primary  malarial  attack  is  followed  by  one  or  more 
relapses  or  recurrences.  By  recurrences  I  mean  the  appearance  of  symptoms 
due  to  the  same  group  of  parasites  causing  the  original  infection,  and  not  to  a 
reinfection  by  another  group.  So  common  are  recurrences  in  malaria  that 
a  prevalent  belief  is  that  "once  a  victim  of  malaria,  always  a  sufferer  from 
the  disease";  while  this  belief  is  unfounded,  recurrences  often  do  persist  for 
months,  and  sometimes,  although  very  rarely,  for  years.  They  are  most 
common  and  persistent  in  the  aestivo-autumnal  infections,  as  would  be  expected 
from  the  greater  resistance  of  these  infections  to  treatment. 

To  the  clinician  the  time  elapsing  between  the  initial  attack  and  the 
recurrences  is  one  of  the  greatest  interest,  while  to  the  investigator  the  etiology 
of  recurrences  and  the  modus  operandi  have  proven  a  fruitful  field  for  controversy 
and,  from  the  very  nature  of  the  problem,  of  theoretical  deduction. 

Time  of  Recurrence. — Authorities  differ  somewhat  as  to  the  time  of 
recurrence  in  the  different  types  of  malarial  infection,  and  when  we  consider 
the  difficulty  of  ruling  out  reinfections,  especially  in  those  who  reside  in  a 
malarial  locality,  the  slight  difference  in  the  time  as  given  by  various  observers 
is  indeed  surprising.  In  malarious  regions  it  is  obviously  impossible,  in  many 
instances,  to  be  sure  that  the  reappearance  of  symptoms  is  not  due  to  reinfection, 
unless  a  different  species  of  plasmodium  be  present  than  that  found  during  the 
initial  attack.  As  a  basis  for  the  computation  of  the  time  of  recurrence,  Celli 
reckons  "as  recurrent  every  case  of  fever  which  repeats  itself  in  the  same 


240      LATENT,  MASKED  AND  RECURRENT  MALARIAL  FEVERS. 

individual  from  the  July  of  one  year  to  the  end  of  June  of  the  following  year, 
or  during  all  the  cycle  of  the  same  yearly  epidemic."  While,  of  course,  errors 
are  bound  to  occur  with  this  method  of  computing  recurrences,  Celli  believes, 
and  I  think  justly,  that  for  practical  purposes  it  is  as  perfect  as  is  possible  under 
the  circumstances.  I  have  used  this  method  in  compiling  the  table  of  recurrences 
which  follows,  but  have  taken  the  further  precausion  of  selecting  only  those 
cases  which  I  am  reasonably  sure  could  not  have  become  reinfected. 

Bonus,  an  investigator  working  in  Senegal,  found  that  recurrences  took 
place  preferably  upon  the  seventh,  fourteenth,  twenty-first  and  twenty-eighth 
day  after  the  initial  attack.  Of  226  cases,  128  relapsed,  and  of  these  18  relapsed 
upon  the  seventh  day,  64  on  the  fourteenth,  31  on  the  twenty- first,  and  nine  on 
the  twenty-eighth  day.  Ninety-eight  cases  relapsed  irregularly  on  the  ninth, 
tenth,  sixteenth,  and  twentieth  days.  All  of  the  cases  took  quinine  at  the  time 
of  the  attack.  Barudel  from  his  observations,  concludes  that  quotidian  fever 
most  frequently  relapses  upon  the  seventh  day,  tertian  upon  the  fourteenth,  and 
quartan  upon  the  twentieth. 

Mariotti-Bianchi  concludes  that  benign  tertian  infections  relapse  between 
the  fifth  and  eighteenth  days  after  infection,  while  aestivo-autumnal  fevers 
relapse  between  five  and  twenty-one  days,  but  frequently  between  five  and 
nine  days  after  the  initial  attack. 

Zieman  found  that  in  West  Africa  aestivo-autumnal  infections  relapsed 
between  nine  and  twelve  days  after  the  primary  attack,  which,  as  he  points  out, 
is  practically  the  same  as  the  incubation  period. 

Werlhof,  from  his  experience,  decides  that  tertian  infections  relapse  most 
frequently  in  the  second,  and  quartan  in  the  third  week,  while  Duden  claims 
that  on  the  east  coast  of  Africa,  quotidian  fever  relapses  almost  invariably  upon 
the  seventh  day. 

Authentic  recurrences  after  long  intervals  of  time  are  rare,  but  such  cases 
unquestionably  occur.  Thayer  relates  an  interesting  example  and  Mariotti- 
Bianchi  observed  in  tertian  infections  recurrences  between  three  and  thirteen 
months,  and  in  aestivo-autumnal  fevers,  between  four  and  eight  months  apart. 
V.  Leyden  observed  a  recurrence  of  a  malarial  infection  three  years  after  the 
initial  attack,  and  Schilling  has  observed  recurrences  after  eight  and  a  half 
months  and  after  two  and  a  half  years.  As  regards  recurrences  after  such  long 
intervals  as  two  or  three  years  I  agree  with  Mannaberg  that  the  evidence  is  not 
sufficient  to  prove  undeniably  that  the  so-called  recurrences  were  not  reinfections, 
and  such  cases  appear  to  me  to  be  very  doubtful. 

The  following  table  of  recurrences  in  aestivo-autumnal  and  tertian  malaria 
are  prepared  from  carefully  selected  cases  in  which  reinfection  was  considered 
at  least  very  improbable,  and  which,  I  believe,  may  be  considered  as  portray- 
ing the  exact  length  of  time  occurring  between  the  relapses  in  these  types  of 
malarial  fevers.  The  patients  were  all  American  soldiers  observed  in  hospital 
and  thoroughly  treated  with  quinine  during  the  active  symptoms,  while  most 
of  them  received  prophylactic  doses  of  quinine  once  a  week,  which  undoubtedly 
delayed  somewhat  the  relapses  in  the  men  so  treated. 

Aestivo-autumnal  Tertian  Recurrences. — Time  of  the  Various  Recur- 
rences in  55  cases  of  Tertian  Aestivo-autumnal  Malarial  Infection. 


LATENT,    MASKED    AND    RECURRENT    MALARIAL    FEVERS. 


241 


Initial  attack 


Oct. 

Nov. 

Feb. 

Nov. 

Mar. 

Dec. 

Jan. 

Feb. 

Dec. 

Feb. 

Feb. 

Dec. 

Mar. 

Nov. 

Nov. 

Feb. 

Oct. 

Aug. 

Mar. 

Feb. 

Dec. 

Jan. 

Jan. 

Oct. 

Nov. 

Mar. 

Feb. 

Dec. 

Oct. 

Jan. 

Jan. 

Jan. 

Jan. 

Oct. 

Jan. 

Oct. 

Jan. 

Oct. 

Feb. 

Aug. 

Nov. 

Sept. 

Oct. 

Oct. 

Aug. 

Sept. 

Oct. 


12 
19 


3° 

8 

24 

12 

24 

6 

6 

25 
1 
29 
14 
4 
3° 
29 

17 
4 
3° 
26 
1 1 


29 

17 

1 

19 
20 

J9 
19 
18 

25 

2  1 
30 
13 
27 


17 

13 
6 

31 


First 
recurrence 


10  days 
12  days 
1  5  days 

18  days 

19  days 

19  days 

20  days 
20  days 
20  days 
20  days 

20  days 

2 1  days 

22  days 
22  days 
24  days 
24  days 
24  days 
24  days 

24  days 

25  days 

26  days 
26  days 

26  days 

27  days 
27  days 

27  days 

28  days 

28  days 

29  days 

30  days 
30  days 
30  days 

32  days 

33  days 

34  days 
34  days 
34  days 
36  days 
36  days 
36  days 
36  days 
3  7  days 
38  days 
38  days 
38  days 

41  days 

42  days 


Second 
recurrence 


30  days 


20  days 
30  days 
20  days 


60  days 


20  days 
48  days 
33   days 


20  days 
16  days 
26  days 


16  days 
36  days 
48  days 
22  days 


52  days 
2  1  days 
28  days 
48  days 


30  days 


26  days 
40  days 
50  days 
26  days 
56  days 
66  days 
3  5  days 


Third     Fourth     Fifth 
recurrence  ;  recurrence  recurrence 


36  days 


30  days 
30  days 


38  days 


20  days 
30  days 
90  days 


20  days 
1 5  days 


90  days 


17  days 


49  days 


20  days 


30  days 


90  days 


2 1  days 


30  days 


242 


LATENT,  MASKED  AND  RECURRENT  MALARIAL  FEVERS. 


Case 

No. 

Initial 

attack 

First 
recurrence 

Second 
recurrence 

Third 
recurrence 

Fourth 
recurrence 

Fifth 
recurrence 

4S 

Jan. 

Nov. 

Dec. 

Feb. 

Oct. 

Jan. 

June 

Mar. 

1 

3 

7- 

24 

24 

1S 

14 
3 

4  5  .lays 
46  days 
40  days 

50  days 

51  days 
61  days 
64  days 
80  days 

30  days 
2  r  days 

49 

SO 

51 

24  days 
39  days 

1 56  days 
66  days 

120  days 

41  days 

52 

S3 

54 
5  5 

14  days 
96  days 

20  days 

20  days 

A  consideration  of  this  table  shows  that  the  first  relapse  in  tertian  aestivo- 
autumnal  malaria  occurred  at  periods  varying  from  10  up  to  80  days;  in  none 
of  the  cases  did  a  relapse  occur  before  10  days  after  the  initial  infection,  which 
does  not  agree  with  the  results  obtained  by  Mariotti-Bianchi  and  Zieman, 
who  found  that  this  type  of  malarial  infection  relapsed  most  frequently  in  from 
5  to  20,  and  9  to  12  days,  respectively.  The  administration  of  quinine  in  many 
of  these  cases  probably  delayed  the  relapse,  but  even  so,  it  will  be  noticed  that 
the  great  majority  of  the  cases  did  not  relapse  until  after  the  twenty-fourth  day. 
Taken  in  periods  of  ten  days,  an  analysis  of  the  table  shows  that  six  cases 
recurred  between  the  tenth  and  twentieth  days;  23  between  the  twentieth  and 
thirtieth;  16  between  the  thirtieth  and  fortieth;  five  between  the  fortieth  and 
fiftieth;  and  the  remainder  at  periods  later  than  the  fiftieth  day  from  the  initial 
attack.  The  greatest  number  of  relapses  occurred  between  the  twentieth  and 
thirtieth  days,  namely,  23,  and  almost  as  many  between  the  thirtieth  and  fortieth 
days,  namely,  16.  Of  single  days,  five  cases  recurred  upon  the  twentieth  day; 
five  upon  the  twenty-fourth  day;  four  upon  the  thirty-sixth  day;  and  three  upon 
the  twenty-sixth,  twenty-seventh,  thirtieth,  thirty-fourth,  and  thirty-eighth 
days  after  the  initial  attack. 

In  most  instances  secondary  relapses  occurred  at  longer  intervals  than 
the  primary  one,  although  numerous  exceptions  to  this  rule  will  be  noticed 
in  the  table. 

The  statement  that  the  longer  the  infection  lasts  the  longer  becomes  the 
interval  between  relapses  is  not  borne  out  in  this  series  of  cases,  if  the  majority 
of  the  cases  be  taken  into  account.  Thus  in  Case  16,  relapses  occurred  at 
periods  of  20,  38,  and  30  days;  in  Case  21,  at  periods  of  26,  36,  30,  90,  and  30 
days;  in  Case  27,  at  periods  of  28,  21,  20,  and  21  days;  in  Case  37,  at  periods 
of  34,  26,  and  17  days;  in  Case  51,  at  periods  of  50,  24,  and  41  days;  and  in 
Case  54,  at  periods  of  64,  66,  14,  20,  and  20  days. 

Of  the  55  cases,  36  had  two  relapses;  14,  three  relapses;  4,  four  relapses; 
and  2,  five  relapses.     This  well  illustrates  the  persistency  of  aestivo-autumnal 


LATENT,  MASKED  AND  RECURRENT  MALARIAL  FEVERS. 


243 


infections,  and  their  resistance  to  treatment,  unless  the  treatment  be  continued 
for  a  long  period  of  time. 

A  most  interesting  feature  of  the  aestivo-autumnal  cases  is  the  fact  that 
21  of  them  suffered  from  at  least  two  relapses  when  the  prim  ary  relapse  occurred 
as  long  as  27  days  after  the  initial  attack.  In  the  benign  tertian  infections 
not  a  single  secondary  relapse  occurred  after  the  twenty-sixth  day.  In  the 
aestivo-autumnal  infections  it  will  also  be  noticed  that  no  security  against 
future  recurrences  is  apparent  when  the  primary  relapse  occurs  after  a  long 
period  of  time  from  the  acute  attack,  whereas  in  the  benign  tertian  infections 
one  can  almost  rest  assured  that  secondary  relapses  will  not  occur  if  the  primary 
relapse  occurs  a  month  after  the  initial  attack  of  fever. 

Tertian  Recurrences. — The  following  table  gives  the  data  concerning 
recurrences  in  18  cases  of  benign  tertian  malaria.  The  number  is  small,  but 
while  my  records  contain  data  covering  hundreds  of  tertian  malarial  infections, 
in  only  18  cases  can  I  be  sure  of  genuine  recurrence.  The  vast  majority 
of  tertian  cases,  if  properly  treated,  do  not  recur,  and  very  many  of  them  recover 
spontaneously,  although  in  such  cases  recurrence  is  much  more  common,  and, 
indeed,  may  be  stated  to  be  the  rule. 


Table  of  Recurrences  in  18  Cases  of  Tertian  Malarial  Infection. 


Case 
No. 

Initial 

attack 

First 
recurrence 

Second 
recurrence 

Third 
recurrence 

Fourth 
recurrence 

Fifth 
recurrence 

1 

Nov.  2 
Aug.  4 
Aug.  28 
Nov.  6 
Jan.  17 
Nov.  23 
Oct.   6 
Sept.  17 
Aug.  27 
Feb.  12 
Jan.  17 
July  20 
May  3 
Nov.  1 
Sept.  22 
Sept.  1 
Dec.  13 
Sept.  22 

16  days 

18  days 

19  days 

20  days 

20  days 

21  days 

2  1  days 

2 1  days 

22  days 
22  days 
27  days 
30  days 
30  days 
30  days 

33  days 

3  7  days 
38  days 
41  days 

2 1  days 
20  days 
30  days 
24  days 
32  days 
20  days 
30  days 

22  days 
36  days 
18  days 

2 

3 
4 

26  days 

46  days 

5 
6 

30  days 
26  days 

24  days 

7 

8 

27  days 

9 

10 
1 1 

16  days 

27  days 

12 

13 

I4 

15 

16 

17 

18 

A  consideration  of  this  table  shows  that  tertian  relapses  occurred  at  periods 
of  from  16  to  41  days;  the  shortest  period  after  the  initial  attack  was  16  days, 


244      LATENT,  MASKED  AND  RECURRENT  MALARIAL  FEVERS. 

while  Mariotti-Bianchi  found  that  recurrences  in  benign  tertian  appeared  as 
early  as  live  days  and  not  later  than  iS.  Of  the  18  cases,  relapse  occurred  in  i 
in  16  days;  in  i  in  18  days;  in  i  in  19  days;  in  2  in  20  days;  in  3  in  21  days; 
in  2  in  22  days;  in  1  in  27  days;  in  3  in  30  days;  in  1  in  ^^  days;  in  1  in  37  days; 
in  1  in  38  days,  and  in  1  in  41  days.  Secondary  relapses  occurred  in  10  cases; 
a  third  relapse  in  six  cases;  a  fourth  in  three  cases;  and  a  fifth  in  one  case. 
No  secondary  relapse  occurred  if  the  primary  relapse  occurred  more  than  22 
days  after  the  initial  attack,  and,  therefore,  in  tertian  infections  we  may  say 
that  if  a  relapse  does  not  occur  within  a  month  after  the  initial  attack  there 
is  practically  no  danger  of  future  recurrences. 

A  study  of  the  two  tables  given  enables  us  to  conclude  that  in  aestivo- 
autumnal  tertian  infections,  relapses  occur  most  frequently  between  the  twen- 
tienth  and  fortieth  days  after  the  initial  attack,  and  in  benign  tertian  infections 
between  the  fifteenth  and  twenty-second  days ;  during  these  periods  of  relapse 
as  they  may  be  termed,  quinine  should  be  given  in  full  therapeutic  doses,  and 
increased  to  the  point  of  cinchonism  at  the  appearance  of  the  first  symptoms 
indicative  of  a  malarial  attack.  It  should  be  remembered  that  quinine  was 
given  in  prophylactic  doses,  once  a  week,  to  nearly  all  the  cases  quoted  in  the 
tables,  and  thus  the  occurrence  of  the  relapses  was  undoubtedly  delayed  some- 
what, which  accounts  for  the  difference  in  my  results  and  those  of  others  who 
have  studied  the  subject  in  cases  uninfluenced  by  quinine. 

Etiology  of  Recurrences  and  Latency.  Intracorpuscular  Conjuga- 
tion.— The  etiology  of  recurrent  and  that  of  latent,  malarial  infection  should  be 
considered  together,  as  an  explanation  of  the  one  would  necessarily  explain  the 
other,  since  the  infection  must  be  latent  in  the  system  during  the  periods  be- 
tween the  recurrences.  Many  investigators  have  endeavored  to  explain  recur- 
rence in  malarial  infections,  but  almost  all  of  our  knowledge  of  these  subjects 
is  theoretical  and  incapable  of  proof.  It  is  evident  that  the  plasmodia  must 
exist  in  some  form  in  the  body  during  the  intervals  in  which  no  symptoms  are 
present,  and  I  have  already  shown,  in  considering  the  pathology  of  latent  in- 
fection, that  plasmodia  may  be  demonstrated  in  the  spleen  of  patients  who  have 
died  from  some  other  disease  and  in  whom  no  symptoms  of  malarial  infection 
were  ever  present;  these  plasmodia  did  not  differ  in  appearance  from  those 
observed  in  the  peripheral  blood  in  acute  malarial  attacks,  and,  furthermore, 
were  undergoing  normal  schizogony  within  that  organ,  but  in  numbers  insuffi- 
cient to  produce  clinical  symptoms.  In  such  cases  it  may  be  urged  that  after  a 
certain  period  of  multiplication  the  plasmodia  become  numerous  enough  to 
produce  symptoms  of  malarial  infection,  and  thus  a  relapse  may  follow.  While 
this  is  undoubtedly  true  in  some  instances,  it  will  hardly  account  for  long- 
interval  relapses,  for  it  is  impossible  to  believe  that  the  plasmodia  of  malaria 
continue  to  grow  and  multiply  for  weeks,  and  even  months,  within  the  body  of 
man  without  becoming  numerous  enough  to  produce  clinical  symptoms. 

To  overcome  this  objection,  Bignami  considers  that  the  plasmodium 
exists  in  some  latent  form,  perhaps  encapsulated,  in  the  spleen  or  other  inter- 


LATENT,    MASKED    AND    RECURRENT    MALARIAL   FEVERS.  245 

nal  organ,  which  may  not  be  rendered  visible  with  our  present  staining  methods, 
and  which,  resting  as  a  spore,  is  only  set  free  under  certain  favorable  conditions, 
the  nature  of  which  we  are  ignorant. 

Celli,  in  discussing  this  subject  says,  "How  are  these  recurrences  explained? 
It  is  difficult  to  say;  perhaps  they  depend  on  forms  resulting  from  sexual  multi- 
plication that  remain  in  some  viscera — possibly  the  bone-marrow — and,  from 
time  to  time,  invading  anew  the  blood,  give  rise  to  new  generations  of  the 
asexual  cycle." 

Recently  Schaudinn,  in  an  excellent  study  of  Plasmodium  vivax,  stated 
that  recurrences  are  due  to  parthenogenesis  of  the  macrogametes  which  are  not 
fertilized  by  the  micro  gametes,  and  remain  in  the  blood  of  the  human  host. 
After  a  certain  period  of  time  these  macrogametes  liberate  schizonts  which  pene- 
trate the  erythrocytes,  undergo  schizogony,  and  thus  produce  a  relapse.  This 
process  is  completed  in  from  9  to  1:2  days,  and,  according  to  Zieman  and 
Mariotti-Bianchi,  agrees  with  the  period  in  which  relapses  are  most  frequent. 
Schaudinn's  observations  have  never  been  confirmed  and  it  is  difficult  to  under- 
stand how  such  a  process  explains  relapses  occurring  at  irregular  intervals  as 
shown  in  the  tables  given,  where  it  is  obvious  that  no  regularity  is  present  in  the 
development  of  either  the  primary  relapse  or  of  those  succeeding  it.  How  can 
the  parthenogenesis  of  the  macro  gamete,  which  must  occur  in  a  cyclical  manner, 
be  the  cause  of  relapses  occurring  all  the  way  from  16  to  80  days  after  the 
initial  attack  of  fever  ?  I  cannot  confirm  Schaudinn's  results  in  this  direction, 
and  believe,  with  Celli,  that  the  cause  of  relapse  in  malarial  infection  is  a 
resistant  form  of  the  plasmodium  which  is  capable  of  remaining  unchanged  in 
the  human  body  for  considerable  periods  of  time,  and  which,  under  favorable 
conditions,  undergoes  development,  thus  giving  rise  to  the  symptoms  which  are 
the  evidence  of  a  recurrence.  I  have  been  so  fortunate  as  to  be  able  to  devote 
much  study  to  a  form  of  development  of  the  malarial  plasmodia  within  man, 
which  is  evidently  asexual  in  its  nature,  and  which  results  in  the  production  of  a 
form  of  the  parasite  which  I  believe  is  the  cause  of  latent  and  recurrent  infections. 
To  this  process  I  have  given  the  name  "intracorpuscular  conjugation,'  as  it 
consists  essentially  in  the  conjugation  of  two  malarial  plasmodia  within  the 
infected  red  blood-corpuscle. 

The  Process  of  Intracorpuscular  Conjugation. — In  December,  1905, 
I  described  a  process  of  conjugation  in  the  malarial  plasmodia  taking  place 
within  the  infected  red  cells.  This  process  had  been  described  previously  by 
Ewing,  who  considered  it  of  rare  occurrence  and  of  comparatively  little  signifi- 
cance. He  noted  that  the  process  occurred  in  only  a  certain  proportion  of  the 
cases  studied  by  him  and  that  it  occurs  in  the  first  generations  of  the  infection. 
He  says:  "It  seems  probable  that  conjugation  occurs  in  the  first  generations  of 
infection,  and  becomes  less  frequent  as  the  disease  progresses,  the  infection  in 
the  human  host  thereby  tending  to  limit  itself."  The  material  for  my  own 
studies  upon  this  subject  consisted  of  nearly  300  cases  of  malaria  presenting 
clinical  symptoms,  observed  at  the  U.  S.  Army  General  Hospital  Presidio,  of 


246  LATENT,    MASKED    AND    RECURRENT   MALARIAL    FEVERS. 

San  Francisco,  Cal.,  together  with  over  100  cases  of  latent  infection  observed  at 
the  same  place;  a  series  of  75  latent  cases  in  Filipino  children  studied  at  Camp 
Stotsenburg,  and  96  cases  of  acute  infection  observed  at  that  post  and  in 
Manila;  together  with  acute  infections  observed  at  Fort  Leavenworth,  Kansas. 
As  a  result  of  my  studies,  which  cover  a  period  of  nearly  seven  years,  I  have 
become  convinced  that  intracorpuscular  conjugation  is  not  an  accidental  oc- 
currence of  no  essential  importance  in  the  life  history  of  the  malarial  plasmodia, 
but  is  a  process  which  is  most  essential  and  one  that  occurs  invariably  in  all 
acute  infections  in  which  quinine  has  not  been  given  at  such  a  stage  as  to  pre- 
vent its  occurrence.  In  this  process  I  believe  we  have  the  true  explanation  of 
latency  and  recurrence,  and  that  where  it  does  not  occur  the  malarial  infection 
disappears. 

Morphology  of  Intracorpuscular  Conjugation. — This  form  of  conjuga- 
tion always  occurs  between  two.  young  hayaline  ring-forms  and  is  always 
completed  before  the  formation  of  pigment  begins.  The  process  may  be  divided 
for  convenience  of  description  into  three  stages:  In  the  first  stage,  or  stage 
of  protoplasmic  union,  the  two  young  hyaline  ring-forms,  situated  within  a  red 
corpuscle,  are  seen  to  be  in  contact,  and  careful  examination  demonstrates 
that  at  the  point  of  contact  there  is  a  direct  union  of  the  protoplasm;  in  stained 
specimens  it  will  be  noted  that  the  nuclear  chromatin  of  the  two  parasites  is 
separated  at  this  stage  and  that  union  begins  in  the  protoplasm  of  the  plasmodia. 
In  this  stage  the  chromatin  masses  may  be  situated  at  any  portion  of  the  per- 
iphery of  the  two  "rings,"  but  they  are  very  rarely  seen  in  apposition  at  this 
time.  I  have  been  unable  to  detect  any  differences  in  the  appearance  of  the 
two  conjugating  bodies,  for  while  one  may  occasionally  be  a  little  larger  than 
the  other,  this  is  not  so  as  a  rule,  and  the  chromatin  masses  are  always  of  the 
same  size. 

In  the  second  stage,  which  may  be  designated  as  the  stage  of  complete 
protoplasmic  union,  the  chromatin  masses,  still  distinct,  become  situated  in 
the  protoplasm  of  one  organism,  formed  by  the  gradual  union  of  the  protoplasm 
of  the  two;  the  chromatin  masses  may  be  opposite  one  another  or  at  any 
portion  of  the  periphery  of  the  organism,  sometimes  almost  in  apposition. 
The  complete  union  of  the  protoplasm  of  the  two  plasmodia  results  in  a  more 
or  less  perfect  "ring-shaped"  organism,  slightly  larger  than  either  of  the 
original  plasmodia,  containing  two  masses  of  chromatin,  surrounded  by  achro- 
matic substance. 

The  third  stage  of  the  process,  or  stage  of  chromatic  union,  is  characterized 
by  the  union  of  the  two  masses  of  chromatin,  one  large  mass  resulting.  In 
many  cases  a  very  minute  granule  of  chromatin  is  extruded  from  the  Plas- 
modium before  the  chromatin  union  is  complete.  In  stained  specimens 
the  plasmodium  resulting  from  this  form  of  conjugation  is  larger  than  other 
unpigmented  plasmodia,  and  consists  of  a  mass  of  protoplasm  staining  a 
brilliant  blue  with  Wright's  stain,  enclosing  a  very  large  and  bright  mass  of 
chromatin,  surrounded  by  an  unstained  area.     The  resulting  organism  grows 


LATENT,  MASKED  AND  RECURRENT  MALARIAL  FEVERS.      247 

rapidly,  develops  much  pigment,  and  when  fully  grown,  entirely  fills  the  red 
cells  containing  it,  and  eventually  becomes  free  in  the  blood  plasma. 

Briefly  stated,  then,  intracorpuscular  conjugation  consists  in  the  complete 
and  permanent  union  of  two  unpigmented  plasmodia  within  the  red  blood- 
corpuscle.  It  is  absolutely  necessary,  apparently,  to  the  maintenance  of 
malarial  infection  in  man,  and  in  those  instances  in  which  it  does  not  occur, 
the  plasmodia  undergo  asexual  sporulation  for  a  limited  time  and  then  perish, 
thus  causing  spontaneous  recovery.  It  is  present  most  frequently  in  those  cases 
in  which  the  clinical  symptoms  are  most  severe,  and  is  present  in  all  varieties 
of  malarial  infection,  whether  caused  by  the  tertian,  quartan,  or  aestivo- 
autumnal  plasmodia,  although  most  easily  observed  in  the  aestivo-autumnal 
infections. 

The  Significance  of  the  Process  of  Conjugation  in  the  Protozoa  in 
General. — In  order  to  understand  the  significance  of  intracorpuscular  conjuga- 
tion as  it  occurs  in  the  malarial  plasmodia,  it  is  necessary  to  review  briefly 
the  significance  of  this  process  as  it  occurs  in  the  Protozoa  in  general.  It  may 
be  stated  that  conjugation  has  been  observed  at  some  stage  in  the  life-history 
of  individuals  belonging  to  all  the  classes  of  the  Protozoa.  In  the  Rhizopoda, 
the  Flagellata,  the  Sporozoa  and  the  Infusoria  organisms  are  found  in  which  the 
process  of  conjugation  occurs  and  in  which  it  has  been  thoroughly  studied. 
The  morphological  changes  occurring  in  intracorpuscular  conjugation  of 
the  malarial  plasmodia  are  similar  to  those  occurring  in  the  conjugation  of 
other  protozoan  organisms,  and  it  is  reasonable  to  believe  that  the  significance 
of  the  process  is  also  similar.  We  already  know  that  the  plasmodia  of  malaria 
undergo  sexual  conjugation  during  their  development  within  the  mosquito  and 
that  this  is  absolutely  essential  to  sporulation  or  the  formation  of  the  sporo- 
zoites.  However,  in  contradistinction  to  the  form  of  conjugation  just  described 
as  intracorpuscular  conjugation,  the  conjugating  organisms  are  sexually 
differentiated  in  the  sporogony  of  the  malarial  plasmodia.  In  the  mosquito, 
as  regards  the  malarial  plasmodia,  conjugation  is  a  fertilizing  process  per  se, 
while  intracorpuscular  conjugation  simply  stimulates  the  organism  to  renewed 
activity  and  to  the  formation  of  a  resisting  form  of  the  parasite. 

The  process  of  conjugation  in  the  Protozoa  was  first  observed  and  de- 
scribed by  O.  E.  Muller.  His  work  was  confirmed  by  Balbiani,  who  claimed 
that  certain  of  the  Protozoa  not  only  reproduced  by  simple  division  but  also 
by  conjugation,  the  latter  being  a  sexual  act  leading  to  the  formation  of  the 
young  parasites.  It  is  to  Biitschli  that  we  owe  the  corrected  interpretation  of 
conjugation  in  the  Protozoa.  He  observed  that  continued  reproduction  of 
many  of  these  organisms  by  simple  division  led  eventually  to  the  exhaustion 
of  the  capability  of  division,  and  thus  to  the  death  of  the  organisms.  He, 
therefore,  regarded  the  process  of  conjugation  as  intended  to  bring  about 
.  rejuvenescence  of  the  nearly  exhausted  individuals  of  a  generation  of  organisms. 
Englemann  confirmed  the  interpretation  of  Biitschli,  and  to-day  his  definition 
of  the  process  is  accepted  by  all  zoologists.     Briefly  defined,  conjugation  is  a 


248  LATENT,    MASKED    AND    RECURRENT    MALARIAL    FEVERS. 

process  intended  to  bring  about  a  restoration  of  former  reproductive  activity 
in  exhausted  organisms,  this  result  being  secured  by  a  rejuvenescence  of  the 
vital  activities  of  the  organism. 

Calkins,  in  discussing  this  subject  says:  "The  various  conjugation  phe- 
nomena seen  in  the  Protozoa  seem  to  show  that  each  cycle  starts  with  a  certain 
potential  of  vitality  which  is  gradually  exhausted  in  the  vegetable  activities 
of  the  long  line  of  individuals  formed  by  simple  division  or  by  spore  formation." 
It  is  to  rescue  such  generations  of  organisms  that  conjugation  occurs,  but  it 
also  leads,  in  many  instances,  to  the  production  of  resting  and  resistant  forms 
of  the  Protozoa.  That  it  is  not  a  reproductive  act  in  many  of  the  Protozoa  is 
shown  by  the  fact  that  the  time  consumed  in  conjugation  is  sufficient  for  repro- 
duction by  simple  division  to  occur  many  times;  this  is  well  illustrated  in  those 
Protozoa  in  which  a  resting  stage  succeeds  conjugation. 

In  reviewing  the  phenomena  of  conjugation  in  the  Protozoa  we  find  that 
in  many  of  them,  after  the  union  of  the  conjugants,  a  resting  or  zygote  stage 
results,  which  possesses  greater  resistance  to  injurious  influences  than  the 
original  organisms,  and  in  which  they  remain  latent,  so  to  speak,  no  further 
development  occurring  until  conditions  are  favorable  for  the  existence  of  the 
original  parasites. 

The  conjugation  of  a  protozoon  within  its  intermediate  host  is  purely 
sexual  in  nature  and  is  followed  at  once  by  reproduction.  Such  a  type  of  con- 
jugation should  be  clearly  distinguished  from  that  in  which  there  is  a  union  of 
two  individuals  followed  by  a  period  of  inactivity  or  a  zygote  stage.  The  sexual 
type  occurring  in  an  intermediate  host  is  well  illustrated  in  the  conjugation  of 
the  micro-  and  macrogametes  of  the  malarial  plasmodia  within  the  mosquito's 
stomach,  while  intracorpuscular  conjugation  of  the  same  organisms  is  a  typical 
example  of  asexual  conjugation.  It  is  apparent,  therefore,  that  asexual  con- 
jugation is  not  a  reproductive  act,  but  one  intended  to  preserve  the  function  of 
reproduction  in  a  race  of  organisms  threatened  with  extinction  by  repeated 
division,  or  intended  to  evolve  a  resistant  form  of  the  organism  when  conditions 
are  unfavorable  for  reproduction  in  the  ordinary  way. 

The  Relation  of  Intracorpuscular  Conjugation  to  Latent  and  Recur- 
rent Malarial  Infections. — Having  thus  briefly  reviewed  the  significance  of 
conjugation  in  Protozoa  in  general,  we  are  in  a  position  to  consider  the  signifi- 
cance of  that  peculiar  form  of  conjugation  in  the  malarial  plasmodia  which  I 
have  called  intracorpuscular  conjugation.  The  conjugation  of  malarial 
plasmodia  within  the  infected  red  blood-corpuscle  is  asexual,  it  being  impossible 
to  detect  any  constant  difference  in  the  appearance  of  the  two  conjugants.  It 
occurs  between  two  hyaline  plasmodia  and  is  completed,  so  far  as  can  be  seen,  by 
the  permanent  union  of  both  protoplasm  and  nucleus.  It  occurs  whenever  the 
generations  of  plasmodia  are  in  danger  of  perishing  from  repeated  sporulation 
in  the  usual  manner;  it  is  therefore  most  frequently  observed  during  the  latter 
part  of  the  acute  attacks,  instead  of  before  the  appearance  of  clinical  symptoms. 
As  I  have  stated,  conjugation  occurs  in  many  if  not  almost  all  organisms,  when 


LATENT,    MASKED    AND    RECURRENT    MALARIAL    FEVERS.  249 

unfavorable  conditions  arise,  such  as  exhaustion  from  repeated  division,  in- 
sufficient nutriment,  or  the  presence  of  conditions  in  the  environment  that  are 
unfavorable  to  growth  in  the  usual  manner;  it  has  also  been  shown  that  under 
such  conditions  a  resting  or  zygote  stage  succeeds  conjugation,  in  which  the  usual 
vital  activities  of  the  organism  are  wholly  or  in  part  suspended  until  the  condi- 
tions again  become  favorable,  when  the  vital  activities  are  resumed  and  repro- 
duction occurs  as  before. 

If  we  consider  carefully  the  phenomena  of  intracorpuscular  conjugation  as 
seen  in  the  malarial  plasmodia  it  is  evident  that  they  conform  to  those  observed 
during  conjugation  in  many  of  the  Protozoa,  and  that,  if  there  is  any  value  in 
analogy,  the  conditions  leading  to  the  process  and  its  significance  are  similar. 
Considered  in  this  way,  I  believe  that  intracorpuscular  conjugation  is  easily 
explained,  and  that  the  theory  of  the  etiology  of  latency  and  recurrence  which 
follows  and  which  is  based  upon  this  process  is  one  that  is  worthy  of  careful 
study  and  one  that  is  well  supported  by  the  known  significance  of  conjugation 
in  other  protozoan  organisms.  Intracorpuscular  conjugation  in  malaria  occurs 
after  a  series  of  reproductions  by  spore-formation,  during  which  time  the  initial 
potential  energy  of  the  race  of  plasmodia  has  gradually  declined;  during  this 
same  period  the  clinical  symptoms  of  malaria  have  been  present,  and  the  en- 
vironment of  the  plasmodia  rendered  unfavorable,  perhaps  by  the  administra- 
tion of  drugs,  such  as  quinine;  as  a  consequence,  decreased  ability  to  reproduce 
by  spore -formation  leads  to  intracorpuscular  conjugation,  and  the  formation  of 
a  resistant  form  of  the  plasmodium;  the  process  occurs  within  the  red  blood- 
corpuscle,  because  only  here  can  nutriment  be  obtained  for  further  development. 

When  conjugation  is  completed  by  the  permanent  union  of  the  protoplasm 
and  nucleus  of  the  two  conjugants,  growth  occurs  at  the  expense  of  the  red 
corpuscle,  until  finally  the  entire  cell  is  destroyed,  as  in  schizogony,  and  the 
spherical  pigmented  organism  is  liberated;  this  form  now,  in  all  probability, 
becomes  encysted  and  enters  upon  a  resting  or  zygote  stage,  and  it  is  more  than 
probable  that  it  is  this  stage  that  was  considered  by  Schaudinn  as  a  macro  gamete 
which  by  parthenogenesis  gives  rise  to  recurrences.  The  large  pigmented 
bodies  are  found  in  the  peripheral  blood  in  tertian  and  quartan  infections  at 
any  time  after  their  formation,  but  are  seldom  seen  in  the  peripheral  blood 
in  aestivo-autumnal  infections,  being  found  in  the  spleen  and  bone-marrow. 
They  are  difficult  to  distinguish  from  the  macrogametes  in  tertian  and  quartan 
fevers,  although  they  are  larger  and  contain  less  pigment  and  a  greater  amount 
of  chromatin,  while  in  aestivo-autumnal  infections  they  are  distinguished  from 
the  gametes  by  the  absence  of  the  crescentic  shape. 

This  stage  is  probably  more  resistant  to  injurious  influences,  such  as 
quinine,  than  other  forms  of  the  plasmodia,  and  may  continue  unharmed  in 
one  of  the  internal  organs,  as  in  the  spleen,  or  the  bone-marrow,  for  long  periods 
of  time.  When  conditions  are  favorable  the  cyst  (for,  as  has  been  stated,  the 
organism  is  probably  encysted)  ruptures,  and  liberates  a  generation  of  spores 
which  have  developed  within  it;  these  young  plasmodia  penetrate  the  red 


250  LATENT,    MASKED    AND    RECURRENT    MALARIAL   FEVERS. 

blood-corpuscles  and  undergo  schizogony  in  the  usual  manner.  Latency  is 
thus  rendered  possible  by  the  resistance  of  the  resting  or  zygote  stage,  and  recur- 
rences are  due  to  the  liberation  of  the  young  plasmodia  which  have  developed  in 
the  resting  form,  and  their  subsequent  sporulation  within  the  red  corpuscles. 
In  cases  in  which  this  form  of  conjugation  exists,  numerous  large  pig- 
mented plasmodia  are  present,  both  within  and  external  to  the  red  corpuscles, 
which  show  no  evidence  at  any  time  of  segmentation  or  flagellation;  in  these  the 
pigment  is  small  in  amount  and  distributed  throughout  the  protoplasm  in  an 
irregular  manner,  in  the  form  of  very  fine  granules.  In  aestivo-autumnal  infec- 
tions these  bodies  are  seen  only  in  the  blood  obtained  by  splenic  puncture,  and 
they  are  absent  in  cases  in  which  this  form  of  conjugation  is  absent.  These 
bodies  probably  become  encysted  and  situated  in  some  internal  organ  or  in 
the  bone-marrow.  The  growth  of  the  conjugating  form  within  the  red  cell  is 
rapid  until  the  destruction  of  the  cell  and  the  liberation  of  the  organism;  it 
then  enters  upon  the  resting  stage  and  the  duration  of  this  stage  probably 
varies  with  conditions  present,  but  I  believe  lasts  for  several  days  at  least. 

Reasoning  from  analogy,  this  stage  must  continue  for  some  time,  for, 
as  has  been  shown  by  Biitschli,  Maupas,  and  Hertwig,  in  the  Protozoa,  the  two 
conjugating  organisms  might  by  simple  division  give  rise  to  many  generations 
during  the  time  occupied  in  conjugation,  and  this  is  true  of  every  organism  in 
which  asexual  conjugation  occurs,  so  far  as  I  know.  It  would,  indeed,  be 
strange  if  the  malarial  plasmodia  were  exceptions  to  so  general  a  rule,  and 
therefore  it  follows  that  the  resting  stage  must  continue  for  several  days, 
and  that  intracorpuscular  conjugation,  admitting  that  it  produces  this  form  of 
the  plasmodia,  is  the  most  probable  cause  of  latency  and  recurrence.  The 
periods  of  time  between  relapses,  which  vary  somewhat,  but  are  remarkably 
uniform  when  quinine  has  not  been  administered,  are  explained  by  the  time 
consumed  in  the  completion  of  the  process,  of  intracorpuscular  conjugation, 
and  the  development  of  the  young  plasmodia  within  the  encysted  zygote 
while  the  marked  irregularity  in  the  period  between  relapses  after  quinine  has 
been  administered,  is  explained  by  the  liberation  of  the  young  plasmodia  only 
when  the  environment  becomes  favorable,  i.e.,  when  the  quinine  has  been 
discontinued,  the  quantity  administered  decreased,  or  when  absorption  of  the 
drug  fails  to  occur.  We  thus  see  relapses  quickly  follow  the  discontinuance  of 
quinine  in  all  malarial  regions,  and  Celli,  in  his  suggestion  that  relapses  may 
depend  upon  forms  which  remain  inert  in  some  viscera,  stated  what  is  in  all 
probability  the  true  explanation  of  recurrences  in  malaria,  the  inert  sexual 
bodies  of  Celli  being  the  zygote  or  resting  form  of  the  plasmodia,  produced  by 
intracorpuscular  conjugation.  That  such  a  latent  or  resting  form  of  the  malaria 
plasmodia  is  present  somewhere  in  the  body  in  malarial  infection,  is  proven  by 
the  fact  that  the  withdrawal  of  quinine  in  cases  which  have  been  taking  it 
for  weeks  is  often  promptly  followed  by  a  relapse,  and  the  reappearance  of 
the  plasmodia  in  the  peripheral  blood;  it  is  impossible  to  believe  that  normal 
schizogony  has  occurred  in  such  instances  for  weeks,  even  when  quinine  has 


LATENT,  MASKED  AND  RECURRENT  MALARIAL  FEVERS.      25 1 

been  administered  in  large  doses,  without  producing  symptoms,  and  while, 
as  I  have  already  shown,  in  discussing  the  pathology  of  latent  infections, 
schizogony  does  occur  within  the  spleen  without  symptoms  being  produced, 
it  should  be  remembered  that  in  the  patients  in  which  this  was  observed  no 
quinine  was  being  administered,  and  symptoms  would  probably  have  soon 
appeared  had  the  patients  lived.  The  administration  of  quinine,  even  in  very 
moderate  doses,  has  a  very  marked  effect  upon  intracorpuscular  conjugation 
as  observed  in  the  peripheral  blood,  the  conjugating  plasmodia  disappearing, 
perhaps  collecting  in  the  spleen  or  bone-marrow,  while  in  those  cases  in  which 
the  process  has  not  appeared  it  is  never  observed,  if  quinine  be  administered 
promptly.  This  fact  again  is  a  strong  argument  in  favor  of  the  view  that  this 
form  of  the  plasmodia  is  the  cause  of  recurrences,  for  it  is  well  known  that  pri- 
mary cases  of  malaria  thoroughly  and  promptly  treated  with  quinine  seldom 
relapse,  while  those  which  have  been  treated  improperly  or  in  which  the  in- 
fection has  lasted  for  several  days  are  almost  sure  to  suffer  from  one  or  more 
relapses. 

The  large  pigmented  forms  which  result  from  conjugation  show  no 
morphological  changes  after  the  administration  of  quinine,  and  it  is  evident 
that  this  drug  has  no  effect  upon  this  form  of  plasmodia. 

It  should  be  remembered  that  the  list  of  the  Protozoa  in  which  the  life 
cycle  has  been  followed  through  an  intermediate  host  is  not  very  large,  and, 
therefore,  our  knowledge  of  the  exact  details  of  asexual  and  sexual  conjugation 
in  any  single  organism,  at  all  stages  of  its  development,  is  very  limited.  Among 
the  Haemoflagellates  recent  research  has  confined  the  presence  of  asexual  and 
sexual  conjugation  in  the  life  cycle  of  Trypanosoma  lewisi;  asexual  conjugation 
occurring  in  the  blood  of  the  rat  has  been  studied  in  this  organism  by  Bradford 
and  Plimmer,  Doflein,  and  Stassano;  and  the  researches  of  Prowazek  prove 
that  sexual  conjugation  occurs  in  an  intermediate  host.  This  observer  found 
that  Trypanosoma  lewisi  undergoes  a  portion  of  its  life  cycle  within  the  rat 
louse,  Haematopinus  spinulosum;  after  reaching  the  mid-gut  of  the  louse, 
reduction  occurs  in  the  nucleus,  and  male  and  femate  gametocytes  are  formed, 
which  can  be  easily  distinguished;  sexual  conjugation  between  these  forms 
follows,  the  zygote  becomes  an  ookinete  and  this  eventually  results  in  a  single 
trypanosome,  which  again  infects  the  rat  and  reproduces  as  usual. 

From  the  researches  of  the  investigators  mentioned,  it  is  evident  that  in 
Trypanosoma  lewisi  asexual  conjugation  occurs  in  the  blood  of  the  rat  and 
sexual  conjugation  in  the  mid-gut  of  the  rat  louse,  and  it  is  probable  that 
further  research  will  demonstrate  that  asexual  conjugation  is  constantly 
present  in  those  Protozoa  which  require  an  intermediate  host  for  the  completion 
of  their  life  cycle,  sexual  conjugation  occurring  within  the  intermediate  host, 
and  asexual  conjugation  within  the  definitive  host. 


CHAPTER  V. 

Subcontinued   or    Remittent    Malarial  Fevers;  Mixed  Malarial  Infection;  Chronic 
Malarial  Infection  and  Malarial  Cachexia;  Spontaneous  Recovery. 

Any  of  the  malarial  fevers  may  become  irregular  or  remittent  in  character 
as  regards  the  temperature,  but  the  aestivo-autumnal  infections  are  especially 
prone  to  present  irregularities  in  the  fever,  which  in  many  instances  are  very 
confusing.  A  malarial  fever  may  become  continuous,  irregular,  or  remittent 
in  various  ways,  the  principal  of  which  are:  anticipation  or  retardation  of  the 
paroxysm;  infection  with  more  than  one  group  of  plasmodia  or  with  more 
than  one  species;  and  insufficient  treatment  with  quinine.  In  most  of  these 
infections,  especially  those  due  to  the  aestivo-autumnal  plasmodia,  it  is  very 
seldom  possible  to  demonstrate  the  entire  schizogony  in  the  blood,  but  in  those 
cases  which  are  caused  by  mixed  infections  with  more  than  one  species  of 
Plasmodium,  the  species  present  may  be  easily  demonstrated.  It  is  these 
forms  of  malaria  which  are  so  often  confused  with  other  diseases,  such  as 
typhoid  fever,  in  regions  where  malarial  infections  are  rare. 

Subcontinuous  Fevers  Due  to  the  Tertian  Plasmodium  (Plasmodium 
Vivax). — While  the  great  majority  of  benign  tertian  fevers  are  regularly  inter- 
mittent in  type,  it  is  not  so  very  unusual  to  observe  irregular  or  even  subcon- 
tinued forms  of  tertian  infection.  Thayer  and  Hewetson  describe  a  case  of 
tertian  infection  in  which  the  diagnosis  of  typhoid  fever  was  made  and  I  have 
seen  a  few  cases  in  which  the  temperature  curve  was  slightly  remittent  and  the 
cases  were  at  first  regarded  as  typhoid  fever.  Such  cases  are  rare,  it  being  much 
more  common  to  observe  tertian  cases  in  which  a  double  infection  is  present  and 
in  which  the  paroxysms  are  prolonged,  thus  resulting  in  a  very  atypical  tempera- 
ture curve.  In  these  cases  the  temperature  curve  may  show  an  almost  con- 
tinuous fever  or  it  may  resemble  very  closely  that  of  a  tertian  aestivo-autumnal 
infection. 

An  examination  of  the  blood  in  cases  of  irregular  or  subcontinued  tertain 
fever  generally  shows  numerous  plasmodia  in  various  stages  of  development. 

The  symptoms  of  the  subcontinued  form  do  not  differ  in  character  from 
those  usually  observed  in  tertian  infections,  except  that  they  are  apt  to  be  more 
severe  and  in  some  cases  resemble  closely  those  of  typhoid  fever. 

Subcontinuous  Fevers  Due  to  the  Quartan  Plasmodium  (Plasmodium 
Malariae). — Irregular  and  subcontinued  fevers  due  to  the  quartan  Plasmo- 
dium are  so  rare  as  to  be  of  little  practical  importance.  I  have  observed  but  one 
case  of  quartan  fever  in  which  the  fever  was  of  the  subcontinued  type,  and 
Marchiafava  and  Bignami  state  that  while  they  have  seen  a  few  cases  of  ir- 

252 


OTHER    VARIETIES    OF    THE    MALARIAL    FEVERS.  253 

regularly  intermittent  quartan  fever  they  have  never  observed  one  showing  a 
continuous  fever,  although  Antolisei  and  Feletti  describe  such  cases.  In  the 
case  observed  by  myself  the  blood  showed  quartan  plasmodia  in  all  stages  of 
development  and  the  symptoms  were  very  suggestive  of  typhoid  fever. 

Subcontinued  Fevers  Due  to  the  Aestivo-autumnal  Plasmodia 
(Plasmodium  Falciparum  and  Plasmodium  Falciparum  QuotidianumJ.— 
The  vast  majority  of  irregular  and  subcontinued  malarial  fevers  are  caused 
by  the  aestivo-autumnal  plasmodia,  for  in  this  variety  of  malarial  infection 
the  development  of  the  life  cycle  of  the  plasmodia  is  more  apt  to  be  atypical, 
and  multiple  and  mixed  infections  are  observed  more  frequently  I  agree  with 
Marchiafava  and  Bignami  in  prefering  the  term  "subcontinuous"  to  the  terms 
"remittent"  and  "continuous"  so  frequently  used  in  connection  with  these 
fevers.  I  have  already  mentioned  the  various  ways  in  which  a  malarial  in- 
fection may  become  continuous  or  remittent,  but  will  briefly  recapitulate  here, 
as  it  is  in  the  aestivo-autumnal  infections  that  these  causes  are  most  frequently 
operative: 

1.  The  paroxysms  may  be  prolonged  so  that  they  overlap  each  other,  thus 
causing  a  more  or  less  continuous  temperature  curve. 

2.  The  paroxysms  may  anticipate,  one  beginning  before  the  preceding  one 
ends. 

3.  The  paroxysms  may  be  duplicated. 

4.  There  may  be  a  mixed  infection  with  the  quotidian  and  tertian  aestivo- 
autumnal  plasmodia  or  with  the  benign  tertian  or  the   quartan  plasmodium. 

5.  Quinine  may  be  administered  in  such  doses  as  to  cause  the  temperature 
curve  to  become  atypical  without  curing  the  infection. 

Subcontinued  aestivo-autumnal  infections  may  begin  as  such,  which  is 
frequently  the  case,  or  they  may  gradually  develop  during  a  typical  attack  of 
either  the  tertian  or  quotidian  infection.  When  developing  in  the  latter  manner 
they  are  generally  easy  of  recognition,  but  when  an  aestivo-autumnal  infection 
begins  as  a  subcontinued  fever,  it  is  often  impossible  to  recognize  it  without  an 
examination  of  the  blood,  and,  if  the  plasmodia  are  present  in  but  small  num- 
bers, repeated  examinations  of  the  blood  will  have  to  be  made.  To  depend 
upon  clinical  symptoms  in  the  diagnosis  of  subcontinued  aestivo-autumnal 
malaria  is  to  attempt  the  impossible  in  most  instances,  and  if  there  is  one  thing 
in  the  medical  history  of  this  country  which  should  teach  the  profession  the 
folly  of  attempting  to  diagnose  the  malarial  fevers  by  the  symptoms  alone  it  is 
the  experience  of  our  armies  in  the  camps  throughout  the  South  in  1898  and 
the  experience  of  the  British  army  in  South  Africa  during  the  Boer  War. 

Symptoms. — The  symptoms  of  the  subcontinuous  aestivo-autumnal 
fevers  vary  considerably  in  different  cases,  and  various  types  have  been  described, 
as  the  typhoidal,  the  pneumonic,  and  the  bilious,  but  such  a  classification  is 
loose  and  unscientific  and  undeserving  of  consideration.  It  is  but  rarely  that 
a  case  of  subcontinued  or  remittent  aestivo-autumnal  fever  is  observed  for  a 
period  of  time  sufficient  to  gain  an  adequate  idea  of  its  symptoms  and  course, 


254  OTHER    VARIETIES    OF    THK    MALARIAL    II  VERS. 

as  quinine  is  generally  given  at  the  beginning  of  the  attack  and  the  disease  ar- 
rested. In  those  cases  I  have  observed  the  symptoms  have  varied,  but  on  the 
whole  resembled  those  of  typhoid  fever  very  closely  at  some  time  in  the  course 
of  the  disease.  The  prodromal  symptoms  are  generally  weakness  and  malaise, 
headache,  dull  pains  in  the  muscles  of  the  trunk  and  extremities,  and  loss  of 
appetite.  The  attack  usually  begins  with  slight  chilly  sensations,  a  distinct 
chill  being  observed  but  rarely.  The  patient's  appearance  is  often  very  sug- 
gestive of  early  typhoid,  the  face  being  flushed,  the  eyes  brilliant,  the  conjunc- 
tivae congested,  the  mucous  membranes  hyperaemic,  and  the  skin  hot  and  dry. 
Severe  headache  is  present  and  pain  in  the  muscles  of  the  back  and  legs;  the 
patient  is  very  nervous  and  restless,  sleeping  poorly  and  waking  with  a  start,  and 
there  may  be  slight  delirium.  The  tongue  is  dry  and  coated  and  may  resemble 
very  closely  the  tongue  of  typhoid,  while  nausea  and  vomiting  are  present  and 
diarrhoea  is  a  frequent  symptom.  The  pulse  is  rapid  and  dicrotic  in  character, 
while  the  respirations  are  hurried  and  very  often  superficial.  There  is  often 
present  marked  tenderness  over  the  abdomen,  and  the  spleen  is  enlarged  and 
tender  upon  pressure. 

In  those  cases  which  most  closely  simulate  typhoid  fever — the  so-called 
"typhoid  pernicious  malarial  fever" — the  resemblance  is  indeed  startling — epis- 
taxis,  roseolar  eruption,  gurgling  and  tenderness  in  the  right  iliac  fossa,  the 
cerebral  symptoms  and  the  headache,  all  being  present  in  addition  to  the  symp- 
toms enumerated.  Before  the  discovery  of  the  malarial  plasmodia  such  cases 
caused  much  confusion,  but  there  is  no  difficulty  in  diagnosing  them  to-day  by  the 
aid  of  the  microscope.  It  is  to  this  class  of  cases  that  the  term  "typho-malarial 
fever"  has  been  applied  by  some  observers,  but  the  microscope  has  definitely 
proven  the  falsity  of  this  appellation,  and  we  know  that  there  is  no  such  disease 
entity  as  typho-malarial  fever,  although  there  may  be  a  mixed  infection  with 
typhoid  and  any  of  the  malarial  fevers. 

The  temperature  curve  in  the  subcontinued  aestivo-autumnal  fevers  is 
very  variable,  but  there  may  usually  be  traced  slight  intermissions  corresponding 
to  the  termination  of  the  paroxysms.  In  some  cases,  however,  the  curve  much 
resembles  that  of  typhoid  fever,  there  being  slight  daily  remissions;  this  is  es- 
pecially true  of  the  subcontinued  fevers  due  to  the  quotidian  plasmodium. 
The  chart  shown  is  fairly  typical  of  such  a  fever.     (Chart  No.  16.) 

The  duration  of  the  subcontinued  or  remittent  fevers  may  be  several 
weeks,  but  usually  spontaneous  recovery  or  death  occurs  within  three  weeks. 
If  properly  treated,  the  symptoms  are  easily  controlled  within  a  week,  although 
in  very  rare  instances  the  plasmodia  may  be  very  resistant  to  quinine  and  persist 
for  eight  or  ten  days.  An  examination  of  the  blood,  if  carefully  made  and 
repeated,  if  necessary,  will  invariably  demonstrate  one  or  perhaps  both  of  the 
aestivo-autumnal  stages  of  development.  Very  rarely  a  sporulating  organism 
may  be  seen  in  the  peripheral  blood. 

The  point  of  greatest  importance  to  remember  regarding  subcontinued 
forms  of  malaria  is  that  these  infections  pursue  a  more  or  less  continuous  or 


OTHER    VARIETIES    OF    THE    MALARIAL    FEVERS. 


256  OTHER    VARIETIES    OF    THE    MALARIAL    FEVERS. 

remittent  course  as  regards  the  temperature,  resembling  typhoid  fever  or 
other  febrile  processes  clinically,  and  that  the  only  way  of  quickly  diagnosing 
them  is  by  the  microscopical  examination  of  the  blood.  These  fevers  are  apt 
to  become  pernicious  at  any  time,  and  death  may  occur  suddenly,  so  that  a 
prompt  diagnosis  and  proper  treatment  is  of  the  very  greatest  importance. 

Mixed  Malarial  Infections. — Any  of  the  species  of  the  malarial  plasmodia 
may  occur  together,  thus  causing  what  is  known  as  a  mixed  or  combined 
infection.  Such  infections  are  very  common  in  some  localities  and  are  rare 
in  others,  as  would  be  expected.  In  those  localities  in  which  more  than  one 
type  of  malaria  is  common,  mixed  infections  are  common,  while  in  those  in 
which  only  one  type  of  infection  occurs,  they  will  be  absent  or  very  rarely 
occur  as  imported  cases. 

In  2,803  cases  of  malaria  occurring  in  soldiers  who  contracted  their  infection 
in  Cuba  and  in  the  Philippines,  I  observed  but  61  cases  of  mixed  infection, 
of  which  51  were  combined  tertian  and  tertian  aestivo-autumnal  infections; 
nine  combined  tertian  and  quotidian  aestivo-autumnal  infections;  and  one 
a  combined  tertian  and  quartan  infection.  This  is  a  very  small  percentage 
of  mixed  infections,  but  is  explainable  by  the  fact  that  in  most  of  the  localities 
in  which  these  men  had  been,  the  aestivo-autumnal  infections  were  practically 
the  only  infections  present,  and  thus  the  men  did  not  become  infected  with 
the  other  varieties.  In  mixed  infections  the  temperature  chart  is  apt  to  be 
irregular  or  remittent,  but  very  often  one  type  of  plasmodium  may  so  predomi- 
nate in  numbers  that  the  infection  will  present  the  characteristic  symptoms 
caused  by  that  organism.  Thus  we  may  have  combined  infection  with 
aestivo-autumnal  and  tertian  plasmodia  in  which  the  aestivo-autumnal  plasmo- 
dia are  so  much  more  numerous  than  the  tertian,  that  the  case  will  present  the 
symptoms  of  an  aestivo-autumnal  infection.  As  would  be  expected,  some 
very  peculiar  temperature  charts  are  observed  in  these  mixed  infections,  and 
the  symptoms  are  often  so  anomalous  that  a  diagnosis  cannot  be  made  without 
the  aid  of  the  microscope. 

Chart  No.  17  is  a  beautiful  illustration  of  a  case  in  which  there  existed 
a  combined  infection  with  the  tertian  and  the  tertian  aestivo-autumnal  plasmo- 
dium and  in  which  the  aestivo-autumnal  and  tertian  paroxysms  occurred 
independently  of  one  another.  This  is  the  only  instance  of  the  kind  I  have 
ever  observed  and  I  believe  that  this  chart  is  unique  in  the  literature  of  the 
malarial  fevers.  A  blood  examination  in  this  case  demonstrated  the  presence  of 
both  species  of  plasmodium,  and  the  life  cycle  of  the  tertian  plasmodium  could 
be  easily  followed  in  the  peripheral  blood  and  correpsonded  with  the  chart. 

The  Symptoms  of  Chronic  Malarial  Infection  and  Malarial  Cachexia. 
— I  have  already  described  the  pathology  of  chronic  malarial  infection  and 
malarial  cachexia  and  have  spoken  of  the  changes  occurring  in  the  blood  in  such 
infections. 

In  patients  who  have  suffered  from  repeated  attacks  of  malarial  fever, 
which  have  not  been  properly  treated,  there  develops  a  peculiar  condition,  the 


OTHER    VARIETIES    OF    THE    MALARIAL    FEVERS. 


257 


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258  OTHER    VARIETIES    OF    THE    MALARIAL    FEVERS. 

most  characteristic  symptoms  of  which  are  a  more  or  less  severe  anemia  and  a 
greatly  enlarged  spleen.  This  so-called  malarial  cachexia  is  most  frequently 
observed  in  tropical  regions  in  which  the  aestivo-autumnal  infections  are 
endemic  and  least  frequently  in  localities  in  which  only  tertian  fevers  are 
present.  It  is  especially  apt  to  develop  after  latent  and  masked  infections, 
which  have  gone  untreated  because  unrecognized. 

While  malarial  cachexia  is  a  common  condition  in  natives  of  tropical 
regions,  and  in  Europeans  who  have  long  resided  in  such  regions,  it  is  by  no 
means  as  common  as  many  writers  would  lead  us  to  believe.  Since  the  dis- 
covery that  kala-azar  is  a  distinct  disease,  for  instance,  it  has  become  necessary 
to  revise  our  conceptions  of  the  pathology  and  symptomatology  of  malarial 
cachexia,  for  kala-azar  was  long  believed  to  be  a  chronic  malarial  infection 
and  many  of  our  classical  descriptions  of  that  condition  were  based  upon  the 
symptoms  and  pathology  of  kala-azar.  We  now  know  that  the  enlargement 
of  ihe  spleen,  which  is  used  by  some  authorities  as  an  index  of  malarial  endem- 
icity,  can  no  longer  be  so  used  in  India,  for  this  is  one  of  the  constant  and  one  of 
the  most  important  symptoms  of  kala-azar.  We  should  be  careful,  then,  in 
making  a  diagnosis  of  malarial  cachexia,  remembering  that  other  tropical 
diseases  produce  symptoms  resembling  very  closely  those  present  in  chronic 
malarial  infection,  and  that  some  of  our  most  important  symptoms  may  be 
due  to  an  unrecognized  condition,  as  was  the  case  with  kala-azar. 

Chronic  malarial  infection  is  characterized,  as  a  rule,  by  repeated  attacks 
of  fever  and  the  gradual  development  of  anaemia  and  an  enlarged  spleen.  The 
patients  suffering  from  malarial  cachexia  present  a  peculiar  yellowish  or  grayish 
hue  of  the  skin,  or  an  earthy  pallor,  while  the  mucous  membranes  are  very 
pale,  due  to  the  anaemia  which  is  invariably  present.  There  is  a  loss  of 
appetite,  diarrhoea,  dyspnoea,  emaciation,  and  a  general  condition  of  nervous 
exhaustion.  Between  the  febrile  attacks  the  temperature  may  be  normal, 
but  generally  shows  a  slight  rise  toward  evening;  it  seldom  reaches  1020  F. 
The  condition  is  especially  frequent  in  children  living  in  tropical  localities. 
It  should  be  remembered  that  in  many  instances  repeated  attacks  of  malaria 
do  not  produce  the  symptoms  of  malarial  cachexia,  and  this  is  well  illustrated 
in  our  soldiers,  hundreds  of  whom  have  suffered  from  numerous  attacks  of 
malaria,  but  who  have  never  developed  the  symptoms  of  cachexia,  being,  between 
the  attacks,  in  vigorous  health  and  presenting  no  anaemia  of  consequence. 
In  many  patients  suffering  from  malarial  cachexia,  epistaxis  and  hemorrhages 
into  the  mucous  membranes  are  common  symptoms,  due  to  the  hydraemic 
condition  of  the  blood,  while  in  others  albuminuria,  oedema,  and  nephritis  are 
frequently  observed. 

The  anaemia  which  is  present  in  malarial  cachexia  partakes  of  the  character 
of  a  secondary  anaemia,  the  red  cells  being  reduced  to  2,000,000  or  less  per 
cubic  millimeter,  while  there  is  a  marked  increase  in  the  large  mononuclear 
leucocytes  and  a  corresponding  decrease  in  the  haemoglobin.  In  some  instances 
the  blood  becomes  so  impoverished  that  a  recurrent  attack  of  the  fever  may 


OTHER    VARIETIES    OF    THE    MALARIAL   FEVERS.  259 

prove  fatal,  if  the  pla?modia  are  numerous,  because  of  the  added  acute  de- 
struction of  the  red  corpuscles,  and  after  such  an  attack  a  pernicious  form  of 
anaemia  may  develop.  In  such  cases  the  blood  findings  differ  from  those  of 
primary  pernicious  anaemia  in  the  absence  of  nucleated  red  cells  and  the  slight 
degree  of  poikilocytosis. 

Enlargement  of  the  spleen  is  a  common  condition  in  malarial  cachexia,  but 
not  an  invariable  one.  I  have  observed  many  cases  of  chronic  malarial  in- 
fection in  which  the  spleen  was  but  little,  if  any,  enlarged.  In  old  cases  the 
organ  may  be  enormously  enlarged,  reaching  as  low  as  the  crest  of  the  ilium,  but 
as  a  rule  it  does  not  extend  more  than  4  to  8  cm.  below  the  border  of  the  ribs. 
It  is  firm  and  not  painful  upon  palpation.  The  liver  is  usually  enlarged  and 
pain  is  often  complained  of  over  the  hypochondria. 

Neuralgic  affections  have  long  been  considered  by  some  observers  to  be  due 
to  malarial  poisoning,  but  I  believe  that  it  is  only  occasionally  that  malaria  is  the 
cause  of  neuralgia.  The  long-continued  malarial  infection  renders  these 
patients  especially  liable  to  acute  infectious  diseases  and  slight  injuries  are 
often  attended  by  suppuration,  phlegmonous  inflammation,  or  haemorrhage. 

Marchiafava  and  Bignami  state  that  it  has  never  been  their  experience  to 
observe  in  patients  suffering  from  malarial  cachexia  grave  infections  with  many 
parasites  in  the  blood,  but  that  there  are  always  a  few  parasites  and  very  little 
melanaemia.  I  agree  with  them  in  this  and  would  impress  upon  the  student  of 
this  subject  that  malarial  cachexia  cannot  always  be  determined  by  a  causal 
examination  of  the  blood,  as  the  plasraodia  will  not  be  present  in  any  number 
except  when  acute  symptoms  are  present  and  in  many  cases  melanaemia  may  be 
absent. 

Spontaneous  Recovery. — By  spontaneous  recovery  we  mean  the  disap- 
pearance of  a  malarial  infection  without  the  intervention  of  medicines;  in 
other  words,  the  cure  of  the  infection  by  the  infected  individual.  In  the  pre- 
quinine  days  this  was  the  way  in  which  most  malarial  infections  were  cured,  and, 
as  often  happens,  the  physician  received  the  credit  due  to  Nature.  To  what, 
then,  when  spontaneous  recovery  occurs,  is  it  due?  We  are  unable  to  answer 
this  question  exactly,  but  some  deductions  may  be  drawn  from  the  examination 
of  the  blood  in  such  cases,  and  the  known  facts  regarding. the  defensive  agencies 
of  the  human  body. 

The  examination  of  the  blood  in  cases  which  are  undergoing  spontaneous 
recovery  shows  a  gradual  diminution  in  the  number  of  the  plasmodia  present  as 
improvement  occurs  in  the  condition  of  the  patient.  Together  with  this  diminu- 
tion, which  is  progressive,  there  occur  certain  degenerative  changes  in  the 
plasmodia,  such  as  vacuolation  and  fragmentation,  and  numerous  pigmented 
leucococytes,  macrophages,  and  much  free  pigment  appears  in  the  blood. 
Many  times,  in  cases  undergoing  spontaneous  recovery,  the  entire  life  cycle  of 
the  plasmodium  may  be  observed  in  the  blood,  in  tertian  and  quartan  fever,  but 
the  organisms  are  so  few  in  number  that  no  symptoms  of  the  infection  are 
observed. 


260  OTHER    VARIETIES    OF    THE    MALARIAL    FEVERS. 

Metchnikofi  and  his  adherents  have  laid  much  stress  upon  the  relation  of 
phagocytosis  to  spontaneous  recovery,  and  although  it  is  doubtless  a  factor  in 
the  production  of  spontaneous  recovery  in  malaria,  there  are  other  factors 
present  which  arc  doubtless  of  as  great  importance.  It  must,  I  think,  be 
admitted  that  the  phagocytes,  by  destroying  numerous  plasmodia,  and  removing 
from  the  blood  large  quantities  of  pigment  and  excrementitious  matter,  greatly 
help  in  producing. recovery  from  the  infection,  but  phagocytosis  per  se  is  not  the 
sole  cause  of  spontaneous  recovery,  which  is  undoubtedly  due  to  several  factors, 
some  of  which  are  active  in  one  case  and  some  in  another. 

According  as  we  are  followers  of  Ehrlich's  or  of  Metchnikoff 's  theory  of  im- 
munity, we  may  explain  differently  the  occurrence  of  spontaneous  recovery  in 
malaria,  but  I  believe  that  both  theories  should  be  applied  in  this  instance,  as 
it  is  obvious  that  strict  adherence  to  one  does  injustice  to  the  other,  and  that 
both  present  valuable  evidence  helping  us  to  understand  the  process  under  dis- 
cussion. For  instance,  there  can  be  no  question  but  that  in  malaria  the  phe- 
nomenon known  as  phagocytosis  is  of  immense  importance  in  the  production 
of  spontaneous  recovery,  and  to  entirely  ignore  it  in  favor  of  Ehrlich's  views' 
would  be  both  unjust  and  unscientific.  For  this  reason  I  have  endeavored  to 
view  this  subject  from  a  somewhat  broader  standpoint  than  is  usual,  and  in 
doing  so  I  have  been  inevitably  led  to  include  both  Ehrlich's  and  Metchnikoff's 
theories  in  the  explanation  of  the  process. 

I  believe  that  spontaneous  recovery  in  malaria  may  be  brought  about  by  the 
following  factors: 

i.  The  presence  in  the  blood  serum  of  antiplasmodial  and  antitoxic 
principles,  preexistent  in  the  serum  or  liberated  by  phagolysis  of  leucocytes,  or 
both. 

2.  Absorption  of  the  malarial  toxin  or  toxins  by  the  leucocyte. 

3.  Formation  and  excretion  of  antiplasmodial  and  antitoxic  materials  by 
the  leucocytes. 

4.  Phagocytosis. 

5.  Inability  to  produce  the  "latent  phase  of  the  plasmodium"  which  may 
depend  upon  any  of  the  above  factors  or  may  be  due  to  other  causes. 

6.  A  partial  natural  immunity,  dependent  upon  the  factors  discussed  in 
the  chapter  dealing  with  Immunity. 

In  addition  to  the  factors  enumerated  and  which  are  of  prime  importance 
in  the  production  of  spontaneous  recovery,  there  are  secondary  factors  which 
are  active  in  assisdng  the  natural  body  defenses,  such  as  good  nursing,  good 
food,  rest  and  quiet,  and  the  prevention  of  reinfection. 

It  is  certainly  most  probable  that  there  are  present  in  the  blood  serum  in 
malaria  certain  antiplasmodial  and  antitoxic  substances  which  serve  to  over- 
come the  infection,  and  that  other  substances  of  this  nature  are  evolved  during 
the  progress  of  the  disease.  The  degenerative  changes  observed  in  the 
plasmodia  during  spontaneous  recovery  are  indicative  of  the  existence  of  such 
bodies,  and  while  Mannaberg  believes  that  the  fever  present  is  detrimental  to 


OTHER    VARIETIES    OF    THE    MALARIAL    FEVERS.  261 

the  growth  of  the  parasites,  this  can  hardly  be  so,  for  often  the  cases  showing 
the  highest  temperatures  present  large  numbers  of  plasmodia,  all  of  them  in 
normal  condition;  Marchiafava  leans  to  the  theory  that  in  malaria,  as  in  bacterial 
diseases,  the  parasite  gradually  loses  its  virulence,  but  in  opposition  to  this  it 
may  be  urged  that  the  cause  of  malaria  is  not  a  bacterium,  but  belongs  to  the 
animal  kingdom,  and  that  there  is  no  evidence  of  such  a  diminution  in  virulence, 
and  even  in  the  case  of  bacteria  a  diminution  in  virulence  does  not  cause  de- 
generative changes  in  the  organism.  If,  then,  neither  the  fever  nor  diminished 
virulence  can  result  in  degeneration  of  the  plasmodia,  it  is,  I  believe,  justifiable 
to  conclude  that  it  is  due  to  antiplasmodial  substances  existing  either  pre- 
formed in  the  blood  serum  or  produced  in  reply  to  the  stimulation  of  the 
plasmodia.  The  antiplasmodial  bodies  which  produce  degeneration  and  frag- 
mentation of  the  plasmodia  probably  consist  of  plasmodicidal  and  plasmodilytic 
bodies. 

In  addition  to  antiplasmodial  bodies  it  is  evident  that  antitoxic  bodies 
are  present  in  many  instances  and  thus  are  explained  those  cases  in  which 
numerous  plasmodia  may  develop  for  weeks  without  the  appearance  of 
symptoms  and  those  cases  in  which  repeated  infection  has  resulted  in  very  slight 
symptoms  only,  even  though  many  plasmodia  are  present  in  the  blood.  The 
origin  of  these  antiplasmodial  and  antitoxic  bodies  is  unknown,  but  according 
to  Metchnikoff  may  be  the  leucocytes  or,  according  to  Ehrlich,  of  indefinite 
origin,  being  found  only  in  the  serum. 

Phagocytosis  has  already  been  discussed,  but  it  is  evidently  of  great  impor- 
tance in  the  production  of  spontaneous  recovery.  The  malarial  plasmodia, 
whether  living  or  dead,  are  engulfed  by  the  phagocytic  cells  and  destroyed, 
and  though  in  many  cases  there  exists  an  apparent  decrease  in  the  leucocytes 
in  the  peripheral  blood  in  malaria,  we  must  remember  that  there  is  an  increase 
in  the  large  mononuclear  leucocyte,  and  that,  after  all,  the  decrease  may  be 
only  apparent,  the  greater  number  of  the  leucocytes  being  collected  in  the  internal 
organs,  where  they  are  acting  as  phagocytes.  There  is  much  anatomical  evi- 
dence in  favor  of  this  view,  for  in  sections  of  the  spleen  and  the  bone-marrow, 
the  phagocytic  cells  are  present  in  immense  numbers  in  cases  dying  of 
pernicious  malaria. 

The  process  of  intracorpuscular  conjugation,  or,  rather,  its  absence,  is 
of  great  importance  in  the  production  of  spontaneous  recovery.  Unless  the 
resistant  form  produced  by  conjugation  is  present,  the  malarial  infection  will 
disappear  in  time  as  the  initial  potential  energy  of  the  race  of  plasmodia  will 
become  exhausted  after  a  series  of  reproductions.  When,  therefore,  for  any 
reason,  intracorpuscular  conjugation  does  not  occur  during  a  malarial  infection, 
spontaneous  recovery  must  necessarily  follow  after  a  certain  period  of  time. 

I  have  already  considered  the  factors  at  work  in  the  production  of  immunity 
and,  where  the  immunity  is  only  partial,  these  factors  are  of  importance  in  the 
explanation  of  the  cause  of  spontaneous  recovery. 

Often,  however,  spontaneous  recovery  is  thought  to  have  occurred  when, 


262  OTHER    VARIETIES    OF    THE    MALARIAL    FEVERS. 

in  reality,  it  has  not.  The  fever  may  disappear,  together  with  many  or  all 
of  the  clinical  symptoms,  only  to  be  followed  in  a  week  or  ten  days  by  a  relapse. 
Often  also  after  spontaneous  recovery  is  thought  to  have  occurred,  an  examina- 
tion of  the  blood  will  demonstrate  the  presence  of  a  few  plasmodia,  and  these 
may  persist  for  weeks  without  causing  any  noticeable  symptoms.  Again,  the 
plasmodia  may  entirely  disappear  from  the  peripheral  blood,  but  may  be  found 
in  numbers  in  the  blood  obtained  by  splenic  puncture.  In  aestivo-autumnal 
infections  especially  we  should  be  very  careful  to  draw  a  sharp  distinction 
between  apparent  and  real  recovery,  and  I  am  convinced,  after  a  large  experience 
with  these  fevers,  that  it  is  impossible  to  say  with  certainty  when  a  patient  is 
cured,  for  relapses  occur  so  frequently  that  a  guarded  statement  concerning 
cure  is  always  advisable. 

Literature  upon  the  Symptomatology  of  Malaria,   Latent  and  Masked  Malaria, 
Recurrences  and  Intracorpuscular  Conjugation. 

The  Symptomatology  of  Malaria. 

The  monographs  upon  Malaria  already  quoted. 
1836.     Maillot.     Traite-     des     fievres     intermittentes.     Paris. 
1882.      Sorel.      Recherches  de  la  glycosurie  d.  les  paludiques.      Bui.  d.  1.  Accad. 

de  Med.,  ii,  p.  5. 
1882.     Range.     Paludisme  et  Diabete,  Archiv.  d.  med.  navale,  p.  36. 

1888.  Mosse.      Recherches  sur  l'excretion  urinaire  apres  les  aeces  de  fievres 
intermittentes.      Revue   de  med.,   viii,   p.    944. 

1889.  Kelsch  and  Kiener.     Maladies  des  pays  chauds.     Paris. 

1892.      Bowie.      Spontaneous   Rupture  of  the   Spleen  in  Ague.     The   Lancet, 
Sept.  17. 

1895.  De  Brun.      Etude  sue  le  pneumo-paludisme,  etc.     Revue  de  Med.,  v,  No. 
1 1. 

1896.  Laveran.      Paludisme.      In  Traite  de  Mddecine  et  de  therapeutique,  vol. 
iii.      Paris. 

1896.  Plehn,  A.  Beitrage  zur  Kentniss  der  tropischen   Malaria    in   Kamerun 
Berlin. 

1897.  Pasminik.  Ueber  malariapsychosen.  Wien.  med.  Woch.,  Nos.  12-13. 
1897.     Osler.     Malarial    Fevers.      In    Allbut's    System    of     Medicine,    vol.    ii, 

London. 

1897.  Marchoux.     Le  paludisms  ay  Senegal.     Ann.  d  l'institut  Pasteur. 

1898.  Yarr.  Malarial  Affections  of  the  Eye.  Jour,  of  Trop.  Med.,  Sept.,  p.  43. 
1898.      Rem-Picci.     Sulle  lesioni  renali   nella    infezione    malarica,  II,  Policlin. 

Nos.  5-6. 
1898.     Thayer,    W.    S.      On    Nephritis   of   Malarial   Origin.      Am.   Jour.    Med. 
Sciences,  Nov.  and  Dec. 

1898.  Campbell.     Malarial  Peripheral  Neuritis.     Jour.  Trop.  Med.,  i,  No.  5. 

1899.  Kipp.      On  Malarial  Keratitis.      N.  Y.  Med.  Record,  August. 

1900.  Spiller.      A  Case  of  Malaria  Presenting  the  Symptoms  of  Disseminated 
Sclerosis.      Am.  Jour.  Med.  Sciences,  December. 

1900.  Osler.     A  Case  of  Multiple  Gangrene  in  Malarial  Fever.      Bull.  Johns 
Hopkins  Hospital. 

1901.  Bell,  J.      Malarial  Coma.     The  Lancet,  p.  527. 


OTHER    VARIETIES    OF    THE    MALARIAL    FEVERS.  263 

1 90 1.  Cardamantis  and  Kanellis.  Les  troubles  Psychiques  dans  le  paludisme 
Prog.  Med. 

1901.  Daniels.  Enlarged  Spleens  and  Malaria.  Thompson  Yates  Labora- 
tory Reports,  vol.  iii,  Part  2,  p.  177. 

1902.  Mathis.  Trois  eas  de  polyne"vrites  palustres.  Revue  de  Med.,  xxii, 
p.  105. 

1903.  Burns,  W.  B.  Malarial  Dysentery.  Jour.  Am.  Med.  Assoc.,  vol.  xli, 
No.  4,  p.  246. 

1903.  Glogner.  Ueber  Darmerkrankungen  bei  Malaria.  Virch.  Archiv.  Bd. 
clxxi,  Heft  2. 

Literature   upon   Latency,    Recurrences,    and   Intracorpuscular 

Conjugation. 

The  monographs  upon  Malaria  already  quoted. 

1900.  Koch.     Deutsch  med.  Wochenschrift,  xxvi,  p.  733. 

1901.  Bassett-Smith.     Jour.  Trop.  Med.,  iv,  No.  11,  p.  178. 
1901.     Glogner.      Virch.  Archiv.,  clxvi,  No.  1,  p.  171. 

1 90 1.      Plehn,  A.      Weiteres  iiber  Malaria,  Immunitat  und  Latenzperiode. 

1 901.  Stephens  and  Christophers.  Rep.  Malarial  Com.  Royal  Soc,  3d  ser., 
p.  6. 

1902.  James.  Scien.  Mem.  Officers  Med.  San.  Depts.  Govt.  India,  New  Se- 
ries, No.  2. 

1902.  Caccini.  The  Duration  of  the  Latency  of  Malaria  after  Primary  Infec- 
tion, etc.,  Jour  Trop.  Med.,  Apr.  15,  p.  119;  May  1,  p.  13;  May  15,  p. 
151;  June  1,  p.   172;  June  15,  p.   186. 

1903.  Craig,  C.  F.  American  Med.,  vi,  p.  145;  ibid.,  1904,  viii,  p.  757  ;  ibid.,  1905, 
x,  pp.  982,  1029. 

1903.     Schilling.    Ein  Malariarezidivn,  etc.,  Deutsche  med.  Wochenschr., No.  10. 

1903.      Mariotti-Bianchi.    Reforma  med.  Rome,  xix,  p.  313. 

1903.      Schaudinn.      Arb.  a.d.  kaiserl.   Gesundheitsamte,  xix,  p.   169. 

1903.  Ewing.      Clinical  Pathology  of  the  Blood.      New  York,  p.  454. 

1904.  Strasser  and  Wolf.  Ueber  Malariarezidiv.,  Blatter  fur  klinische 
Hydrotherapie,    No.    3. 

1906.      Zieman.      Handbuch    der    Tropenkrankheiten,    Mense.      Leipzig. 

1906.  Craig,  C.  F.  Latent  Malarial  Infection  and  Intracorpuscular  Conjuga- 
tion.     Philippine  Jour,  of  Science,  i,  p.  523. 

1907.  Craig,  C.  F.  A  Study  of  Latent  and  Recurrent  Malarial  Infection  and 
the  Significance  of  Intracorpuscular  Conjugation  in  the  Malarial  Plas- 
modia.    Jour,  of  Infectious  Diseases,  vol.  iv,  No.  1,  Jan.  1,  pp.  108—140. 


PART  IV. 

THE  SEQUELAE,  COMPLICATIONS,  AND    PROGNOSIS  OF  THE 

MALARIAL  FEVERS. 


CHAPTER  I. 

The  Sequelae  of  the  Malarial  Fevers. 

If  we  consider  the  lesions  produced  by  malarial  infections  in  the  blood  and 
viscera  in  pernicious  cases  and  the  extensive  changes  occurring  in  the  blood  in 
all  instances  of  malarial  infection,  we  can  easily  understand  the  reason  for 
the  occurrence  of  many  grave  sequelae  of  these  infections.  Properly 
speaking,  the  sequelae  of  a  disease  are  those  affections  developing  after  the 
disease  itself  has  ceased  and  which  are  due  to  poisons  generated  during  the 
course  of  the  disease.  The  toxins  elaborated  during  the  development  of  the 
malarial  plasmodia  within  man  may  give  rise  to  certain  conditions  which 
develop  coincident  with  or  after  the  malarial  infection  has  ceased,  and  these 
must  be  regarded  as  sequelae  of  the  disease.  It  is  not  always  easy  to  differen- 
tiate sequelae  from  complications,  for  in  many  instances  a  certain  morbid  proc- 
ess will  develop  during  an  attack  of  malaria  and  it  will  be  impossible  to  say 
whether  or  not  it  is  the  result  of  the  malarial  infection  or  is  simply  a  complica- 
tion of  the  disease.  In  such  instances  we  must  depend  upon  a  careful  clinical 
survey  of  the  case  and  the  recorded  experience  of  others  in  deciding  the  question. 

The  sequelae  of  malaria  affect  almost  every  organ  and  tissue  in  the  body 
and  will  be  considered  under  the  following  headings:  Sequelae  affecting  the 
Nervous  System,  the  Circulatory  System,  the  Digestive  System,  the  Genito- 
urinary System,  the  Glandular  System,  and  the  Organs  of  Special  Sense. 

1.  Sequelae  Observed  in  the  Nervous  System. — Sequelae  are  not  in- 
frequently observed  in  the  nervous  system  due  to  the  blocking  of  the  brain 
capillaries  by  the  malarial  plasmodia  or  their  products  or  to  certain  toxins 
produced  by  the  plasmodia,  and  are  especially  numerous  following  the  aestivo- 
autumnal  infections.  In  many  instances  the  conditions  are  evanescent  in 
character,  but  in  others  they  may  persist  for  months.  Such  a  case  I  recall,  in 
which  a  paresis  of  one  side  of  the  face  developed  during  an  aestivo-autumnal 
attack,  which  persisted  for  two  months  after  the  disease  was  apparently  cured. 

Not  uncommonly,  after  severe  malarial  attacks,  the  mind  appears  to  be 
sluggish  and  inactive,  memory  being  very  defective,  and  sometimes  an  almost 
stuporous  condition  may  be  present.  While  focal  neuroses  are  uncommon  in 
my  experience,  they  are  described  by  many  observers  as  of  frequent  occurrence. 
Thus  Mannaberg  describes  cases  of  hemiplegis,  aphasia,  paraplegia  and  mono- 
plegias. Sensation  may  be  diminished  or  there  may  be  marked  hyperasthesia. 
Boinet  and  Salabert  report  a  case  of  motor  aphasia,  which  continued  a  month 
after  the  malarial  infection  was  cured,  and  from  which  recovery  finally  ensued. 
Vincent  reports  an  interesting  case  in  which  there  was  paralysis  of  the  extensors 

267 


268       SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARIAL  FEVERS. 

of  the  right  hand  and  aphasia  following  malaria,  while  Sacchi  reports  cases  of 
amaurosis  and  loss  of  the  sense  of  taste  and  smell.  I  have  observed  two  cases 
in  which  aphasia  was  present,  but  both  recovered. 

Affections  of  the  spinal  cord  are  very  rare  as  sequelae  of  the  malarial 
fevers.  Paraplegia  is  the  most  common  form  observed,  accompanied  by 
either  loss  of  sensation  or  hyperasthesia.  I  have  observed  one  case  in  which 
there  was  a  paraplegia,  with  partial  paralysis  of  the  rectum  and  bladder. 
Marchiafava  and  Bignami  describe  cases  in  which  the  symptoms  were  those 
of  bulbar  paralysis. 

It  is  probable  that  some  of  the  cases  reported  as  suffering  from  setpielae  of 
malaria  affecting  the  spinal  cord  have  been  instances  of  infection  with  other 
diseases,  as  beriberi  and  syphilis.  In  tropical  regions  especially,  where  both 
malarial  infections  and  beriberi  are  present,  this  mistake  is  very  likely  to 
occur. 

A  condition  almost  indistinguishable  from  multiple  sclerosis  has  been 
described  by  Torti,  Angelini,  Bignami  and  Bastianelli  and  Canalis,  as  occurring 
after  attacks  of  aestivo-autumnal  malaria.  In  these  cases  the  symptoms  disap- 
peared after  treatment  with  quinine,  but  relapses  occurred  in  some  of  them. 
Kahler  and  Pick  describe  an  ataxic  condition,  or  pseudotabes,  occurring  as  a 
sequela  of  malaria. 

Affections  of  the  peripheral  nerves  are  not  uncommon,  and  many  observers 
have  reported  cases  of  neuritis  following  the  malarial  fevers.  Boinet  and 
Salabert  report  a  case  in  which  there  was  atrophy  of  the  muscles,  diminution  of 
the  tendon  reflex,  and  neuritis.  Multiple  neuritis  has  been  described  as  follow- 
ing aestivo-autumnal  malaria  by  Gowers,  Raymond,  and  Jourdan.  Glogner  has 
studied  very  exhaustively  several  cases  of  polyneuritis  following  malarial  fever, 
the  symptoms  consisting  of  severe  pain  in  the  lower  extremities,  increased  by 
pressure;  formication;  motor  weakness  in  the  legs;  partial  or  total  loss  of  the 
deep  reflexes;  partial  or  total  loss  of  response  to  electrical  stimulation,  and 
oedema.  His  observations  have  been  confirmed  by  those  of  Chiarini  and 
Bardellini,  in  Rome,  and  there  can  be  no  doubt  that  polyneuritis  may  be  a 
sequel  of  the  malarial  infections. 

Bastianelli,  Bignami,  and  Chiarini  have  described  cases  in  which  symp- 
toms similar  to  those  of  electric  chorea  or  "Dubini's  disease"  followed  aestivo- 
autumnal  malarial  infections. 

Neuralgia  is  a  common  sequelae  of  malaria  infections,  although  it  should  be 
added  that  it  is  not  as  common  as  is  generally  supposed.  Many  cases  of  so- 
called"  malarial  neuralgias"  have  in  reality  no  connection  with  malaria,  and 
the  name  is  used  as  a  cloak  for  ignorance  of  the  etiology  of  the  affection.  The 
regions  most  frequently  affected  by  true  malarial  neuralgia  are  the  face  and  the 
lumbar  region.  I  have  observed  one  case  of  severe  intercostal  neuralgia  follow- 
ing aestivo-autumnal  infection,  one  case  of  severe  abdominal  neuralgia,  and  one 
case  of  very  severe  sciatica  following  a  tertian  aestivo-autumnal  attack.  In  all 
of  these  cases  continued  treatment  with  quinine  resulted  in  recovery. 


SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARIAL  FEVERS.       269 

Neurasthenia  not  infrequently  is  observed  following  attacks  of  malaria, 
and  in  our  soldiers  many  instances  of  this  condition  were  observed  during  the 
Philippine  insurrection.  While  it  is  true  that  hardship,  anxiety,  home- 
sickness, and  the  depressing  influences  of  a  tropical  climate  had  a  great  in- 
fluence in  the  production  of  these  cases,  it  must  be  admitted  that  there  were 
numerous  instances  in  which  the  condition  did  not  develop  until  after  repeated 
attacks  of  malaria,  and  that  the  continued  and  vigorous  use  of  quinine  resulted 
in  the  recovery  of  most  of  them. 

Melancholia,  mania,  and  delusional  insanity  occur  as  sequelae  of  the 
malarial  infections.  Manson,  Segard,  and  Pasminik,  as  well  as  other  observers, 
have  described  cases  of  insanity  following  malaria,  uncomplicated  by  heredity 
or  alcohol.  Pasminik  in  5,400  cases  of  malaria  observed  mental  disturbances  in 
to6  cases.  Melancholia  and  delusional  insanity  are  the  most  common  forms 
occurring  as  sequelae  of  malaria,  and  the  duration  of  the  cases  varies  from  less 
than  a  week  to  six  months  or  more.  In  very  many  cases  the  mental  depression 
occurring  with  and  following  the  paroxysms  is  very  great,  and  it  is  a  very  com- 
mon occurrence  for  patients  who  have  suffered  from  malaria  to  complain  for 
weeks  afterward  of  suffering  from  "the  blues"  or  of  ill-defined  forebodings;  an 
exaggeration  of  this  condition  becomes  melancholia  which  I  have  found  to  be 
the  most  common  mental  disturbance  following  malaria.  I  have  observed 
many  cases  of  slight  melancholia  in  soldiers  in  the  Philippines  and  returning 
therefrom,  which  were  undoubtedly  due  to  repeated  malarial  infection,  generally 
of  the  aestivo-autumnal  type,  and  it  has  been  remarkable  how  quickly  the  con- 
dition disappeared  under  the  proper  administration  of  quinine.  I  have  also 
seen  cases  of  mania  and  delusional  insanity  following  malaria  in  which  there 
can  be  no  question  that  the  condition  was  due  to  the  malarial  infection. 

Persistent  insomnia  often  occurs  after  malarial  infection,  especially  among 
Europeans  who  are  residing  in  the  tropics,  and  it  is  sometimes  very  resistant  to 
treatment. 

2.  Sequelae  Observed  in  the  Circulatory  System. — It  may  be  said 
with  truth  that  malaria  has  but  little  effect  upon  the  heart  and  blood-vessels. 
Lancereaux  has  endeavored,  without  success,  to  prove  that  acute  endocarditis 
may  be  caused  by  malaria,  and  he  and  Huchard  claim  that  chronic  arteritis  is 
often  of  malarial  origin.  Their  arguments  are  illogical  and  they  furnish  no  con- 
vincing proof  of  the  truth  of  their  assertions.  It  is  certainly  a  fact  that  no  such 
sequelae  have  been  described  by  those  who  have  studied  malarial  infections  in 
tropical  regions  and  it  is  evident  that  if  such  sequelae  were  present  they  would 
have  been  reported  by  many  different  observers.  When  these  diseases  occur 
with  malarial  infections  they  are  complications  and  not  sequelae. 

3.  Sequelae  Observed  in  the  Digestive  System.— As  a  result  of  the 
localization  of  the  plasmodia  in  the  mucous  membrane  of  the  stomach  or  in- 
testine, a  true  acute  or  chronic  ulcerative  enteritis  may  result,  and,  very  rarely, 
the  formation  of  gastric  ulcers.  Parotitis  has  been  described  by  Lancisi,  but  I 
have  never  observed  a  case.     Mannaberg  describes  haemorrhage  from  the 


2  JO       SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARIAL  FEVERS. 

bowels  in  malarial  cachexia,  and  Pensuti  reports  one  case  in  which  there  was 
atrophy  of  the  mucous  membrane  of  the  stomach.  From  the  results  of  a  large 
number  of  autopsies  upon  patients  dying  of  chronic  dysentery,  most  of  whom 
had  suffered  previously  from  malarial  infection,  I  am  very  much  inclined  to 
doubt  the  occurrence  of  such  cases  as  that  described  by  Pensuti,  as  even  in  the 
cases  autopsied,  which  were  certainly  very  liable  to  such  changes,  atrophy  of  the 
mucous  membrane  of  the  stomach  was  not  common. 

I  have  already  noted  the  occurrence  of  dysenteric  symptoms  in  many  cases 
of  malarial  infection  and  following  such  infections.  It  is  my  belief  that  dysen- 
teric symptoms  are  often  due  to  the  localization  of  the  plasmodia  in  the  mucous 
membrane  of  the  intestine,  and  that  in  rare  instances  chronic  dysentery  may  be 
a  sequela  of  such  infections. 

4.  Sequelae  Observed  in  the  Genito-urinary  System. — Albuminuria 
is  of  very  common  occurrence  along  with  and  following  malarial  infections, 
especially  of  the  aestivo-autumnal  type.  As  a  rule,  it  is  a  complication  of 
malaria  rather  than  a  sequela,  but  I  have  seen  several  cases  in  which  a  persistent 
albuminuria  resulted  from  malarial  infection,  no  other  renal  symptoms  being 
present.  Rem-Picci  has  contributed  much  to  our  knowledge  of  this  subject, 
and  he  divides  the  albuminurias  into  the  febrile,  which  occur  with  the  malarial 
paroxysms,  or  follow  them  at  once,  and  the  postmalarial,  which  persist  after  the 
malarial  attack  and  occur  in  malarial  cachexia. 

Nephritis  both  in  an  acute  and  chronic  form  may  occur  as  a  sequela  of 
malaria,  especially  after  aestivo-autumnal  infections.  That  even  chronic 
nephritis  may  be  induced  by  repeated  malarial  attacks  has  long  been  believed 
by  such  observers  as  Rosenstein,  B artels,  Laveran,  Herz,  McLean,  and  Kelsch 
and  Kiener.  The  latter  authorities  describe  two  forms  of  kidney  affections 
following  malarial  infection,  one  characterized  by  a  congested  kidney,  the  other 
by  an  atrophic  kidney.  They  describe  two  forms  of  nephritis,  the  glomerular 
and  the  granular.  The  glomerular  form  is  divided  into  acute  and  chronic,  the 
first  developing  during  or  immediately  after  the  acute  malarial  infection,  the 
second  during  chronic  infection.  The  clinical  symptoms  are  those  of  acute 
and  chronic  parenchymatous  nephritis.  The  granular  form  is  also  divided  into 
acute  and  chronic,  the  first  developing  in  patients  who  have  suffered  from 
numerous  relapses  of  malaria,  the  clinical  symptoms  being  those  of  subacute 
and  chronic  interstitial  nephritis. 

Rem-Picci,  in  his  exhaustive  and  most  valuable  study  of  nephritis  following 
malaria,  divides  the  condition  into  acute  and  chronic  forms,  the  first  developing 
either  during  or  after  the  malarial  infection,  the  second  developing  insidiously 
after  the  malarial  attack.  The  acute  form  may  be  severe  or  slight  in  character 
and  varies  in  duration.  As  a  rule,  the  prognosis  is  good.  He  finds  that  it  is 
most  common  in  aestivo-autumnal  infections  in  autumn  or  winter,  and  in  young 
rather  than  in  old  people.  The  chronic  form  is  a  true  interstitial  nephritis, 
which  may  develop  without  a  previous  acute  attack.  It  is  much  more  rare  than 
is  the  acute  form. 


SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARIAL  FEVERS.       2hJl 

Thayer,  in  a  valuable  study  of  malarial  nephritis,  states  that  of  112  cases  of 
acute  nephritis  observed  in  the  Johns  Hopkins  Hospital,  21,  or  18.7  per  cent., 
were  of  malarial  origin.  He  observed  four  cases  of  chronic  nephritis  following 
malarial  infection  in  1,832  patients  suffering  from  malaria,  and  in  758  cases  of 
malarial  fever  treated  in  the  wards  of  the  hospital  he  found  that  17.5  per  cent, 
presented  casts  of  the  urinary  tubules  in  the  urine.  He  found  that  nephritis 
was  much  more  common  in  aestivo-autumnal  infections  than  in  either  tertian 
or  quartan,  occurring  in  4.7  per  cent,  of  aestivo-autumnal  infections  as  com- 
pared with  only  2.3  per  cent,  of  all  other  infections  combined. 

From  personal  observation  I  believe  that  some  form  of  nephritis  follows 
aestivo-autumnal  infection  in  at  least  3  per  cent,  of  all  cases,  but  that  it  does  not 
follow  tertian  or  quartan  infections  except  in  rare  instances,  not  over  0.5  of  1 
per  cent,  of  my  tertian  and  quartan  cases  showing  nephritis  as  a  sequela.  In  all 
fatal  cases  of  malaria  some  form  of  nephritis  will  invariably  be  found.  Nephri- 
tis following  malaria  may  be  divided  into  subacute  parenchymatous,  chronic 
parenchymatous,  and  chronic  interstitial  forms,  and  these  forms  do  not  differ  in 
their  symptomatology  from  such  conditions  as  observed  when  occurring  alone  or 
as  a  complication  or  sequelae  of  other  diseases.  The  chronic  forms  may 
develop  insidiously,  but  the  subacute  form  is  always  preceded  by  an  acute 
attack.  Amyloid  degeneration  may  occur  in  certain  cases  of  parenchymatous 
nephritis. 

From  my  own  observations  I  would  say  that  casts  of  the  urinary  tubules 
occur  in  25  per  cent,  of  the  cases  of  aestivo-autumnal  malaria,  and  in  5  per  cent, 
of  all  cases  of  benign  tertian  and  quartan  malaria,  but  that  only  a  comparatively 
small  number  of  these  cases  develop  nephritis. 

Polyuria  is  a  frequent  sequela  of  the  malarial  fevers,  especially  of  the 
aestivo-autumnal  variety,  transient  as  a  rule,  but  in  some  cases  very  persistent. 
I  have  observed  a  large  number  of  cases  of  polyuria  following  malarial  infection, 
and  in  some  instances  the  condition  was  very  marked.  In  one  case  the  amount 
of  urine  passed  during  the  24  hours  varied  from  20,000  to  25,000  cubic  centi- 
meters, and  this  condition  existed  for  several  weeks. 

Glycosuria  is  a  very  rare  sequela  of  aestivo-autumnal  infection,  so  rare  that 
there  is  good  reason  to  doubt  its  occurrence.  Marchiafava  and  Bignami  re- 
port a  case  in  which  glycosuria  developed  during  malarial  cachexia,  but  there  is 
no  proof  that  the  condition  was  due  to  malaria. 

5.  Sequelae  Observed  in  the  Glandular  System. 

The  Liver. — In  cases  which  have  suffered  from  repeated  attacks  of 
malaria,  especially  the  aestivo-autumnal  fevers,  a  condition  known  as  hyper- 
trophic malarial  hepatitis  develops,  characterized  by  enlargement  of  the  organ, 
the  perilobular  tissue  being  increased,  and  the  capillaries  markedly  dilated. 
This  condition,  however,  does  not  cause  much  disturbance  in  the  functional 
activity  of  the  organ,  and  no  clinical  symptoms  are  present  which  are 
characteristic. 

Typical  atrophic  cirrhosis  of  the  liver  is,  I  believe,  very  rarely  the  result  of 


2-J2       SEQUELAE,  COMPLICATION'S,  AND  PROGNOSIS  OF  MALARIAL  FEVERS. 

malarial  infection.  Many  observers  differ  upon  this  point,  but  there  is  no 
evidence  sufficient  to  prove  that  cirrhosis  is  often  the  result  of  such  infection. 
It  is,  of  course,  present  in  some  cases,  but  generally  occurs  as  a  complication  due 
to  some  other  cause.  That  this  is  so  is  evidenced  by  the  fact  that  cirrhosis  of  the 
liver  is  no  more  common  in  intensely  malarial  regions  than  it  is  in  immune 
districts. 

The  Spleen. — I  have  already  mentioned  the  enlargement  of  the  spleen 
occurring  in  patients  who  have  suffered  from  repeated  malarial  attacks,  and  to 
this  enlargement  are  due  certain  other  interesting  sequelae  of  malarial  in- 
fection, such  as  floating  spleen  and  rupture  of  the  organ. 

In  rare  instances  the  enlarged  spleen,  by  its  weight,  sinks  into  the  abdominal 
cavity,  the  ligaments  holding  it  in  place  become  stretched,  and  the  organ  can  be 
felt  as  a  movable  mass  through  the  abdominal  walls.  The  condition  is  known 
as  wandering  or  floating  spleen.  The  symptoms  are  pain  upon  movement,  a 
feeling  of  weight  in  the  abdomen,  and  reflex  disturbances,  such  as  headache, 
nausea,  and  vomiting. 

In  acute  or  subacute  infections  the  spleen  is  generally  very  soft  and 
friable,  and  rarely  this  leads  to  rupture  of  the  organ.  This  result  may  be 
induced  by  blows,  falls,  retching  in  vomiting,  or  sudden  movements  of  the 
body.  The  capsule  may  be  lacerated  or  there  may  be  a  slight  tear  in  one 
region.  Laceration  of  the  capsule  only  occurs  when  the  rupture  is  due  to 
violence.  The  symptoms  are  sharp,  lancinating  pain  in  the  left  side,  and  the 
usual  signs  of  collapse  due  to  hemorrhage.  Death  may  occur  almost  in- 
stantly, or  a  day  or  two  may  pass  before  the  fatal  ending,  depending  entirely 
upon  the  extent  of  the  laceration  and  the  consequent  hemorrhage.  I  have 
observed  two  cases  of  rupture  of  the  spleen  and  one  case  has  been  reported  to 
me  by  Captain  Banta,  of  the  Medical  Corps  of  the  U.  S.  Army.  The  occur- 
rence of  abscess  of  the  spleen  has  been  reported,  following  malarial  infection, 
by  Laveran  and  other  observers.  Fassina  has  collected  seven  cases  in  the  liter- 
ature and  saw  two  himself.  Without  doubt  such  abscesses  have  resulted  from 
bacterial  invasion,  although  the  malarial  infection  may  have  produced  condi- 
tions favoring  the  infection.  The  symptoms  have  been  pain,  swelling,  the 
formation  of  a  tumor,  fever,  and  diarrhoea.  Rupture  of  the  abscess  may 
occur. 

Lymphatic  Glands. — Martin  and  Bodnar  describe  enlargement  and  sub- 
acute inflammation  of  the  lymphatic  glands  as  sequelae  of  chronic  malarial  in- 
fection, accompanied  by  intermittent  or  remittent  fever.  I  have  never  observed 
such  cases,  and  believe  that  they  may  have  been  confused  with  cases  of  climatic 
bubo,  glandular  fever,  or  syphilis.  It  should  also  be  remembered  that  in 
infected  regions,  sleeping  sickness,  in  its  early  stages,  and  kala-azar  might 
easily  be  considered  as  chronic  malarial  conditions  and  the  enlargement  of  the 
glands  present  in  these  diseases  be  regarded  as  of  malarial  origin. 

Orchitis  and  epididymitis  have  been  described  as  sequelae  of  malaria  by 
Berthelon,  Martin,  Magnin,  and  others,  but  a  careful  examination  is  sufficient 


SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARIAL  FEVERS.       273 

to  prove  that  many  of  these  cases  are  based  upon  untrustworthy  evidence, 
although  I  believe  that  a  case  such  as  that  reported  by  Zieman,  in  which  no 
other  cause  could  be  demonstrated  and  the  malarial  plasmodia  were  found 
in  the  blood,  proves  that  such  a  condition  may  very  rarely  occur.  The  cases 
reported  in  which  there  is  good  reason  to  believe  that  the  cause  was  really  ma- 
larial presented  a  remittent  fever,  with  enlargement  of  the  testicles  and  the 
epididymis,  and  some  pain  and  inflammatory  swelling;  the  symptoms  were 
easily  controlled  by  quinine,  but  the  enlargement  lasted  in  some  of  the  cases 
for  months. 

6.  Sequelae  Observed  in  the  Organs  of  Special  Sense. 

The  Eye. — Affections  of  the  eye  are  not  uncommon  as  sequelae  of  malarial 
infections,  especially  in  the  tropics  and  following  aestivo-autumnal  infections. 
I  shall  mention  briefly  the  most  important. 

Amaurosis. — In  severe  malarial  attacks  amaurosis  sometimes  occurs 
during  the  attack,  but  it  also  occurs  as  a  sequela.  One  of  the  first  instances 
of  this  kind  was  reported  by  Jacobi,  in  1868,  and  Chiarini  has  since  reported 
several  cases  in  which  there  was  optic  neuritis.  The  more  chronic  condition 
may  be  followed  by  partial  or  total  loss  of  vision  by  reason  of  atrophy  of  the 
optic  nerve. 

Retino choroiditis  has  been  described  by  Poncet  as  occurring  in  chronic 
malarial  infections,  and  Guarnieri  has  given  in  detail  the  pathological  lesions 
observed  in  such  cases.  He  found  that  the  retinal  capillaries  contained  red 
corpuscles  entirely,  many  of  them  containing  pigmented  plasmodia.  In  the 
choroid  he  found  the  larger  vessels  filled  with  pigmented  leucocytes  and 
many  of  the  leucocytes  contained  parasite-infected  red  corpuscles. 

Keratitis. — In  120  cases  of  malaria  observed  in  the  United  States,  Kipp 
found  keratitis  to  be  present,  and  Poncet,  and  Sedan  and  Levrier  have  seen 
similar  cases. 

Vitreous  Humor. — Bull  reports  17  cases  in  which  haemorrhage  had  oc- 
curred into  the  vitreous  humor,  and  Seely  and,  later,  Sulzer,  described  serous 
engorgement  of  the  vitreous  followed  by  almost  total  blindness.  The  lesion 
consists  in  a  serous  infiltration  of  the  vitreous,  and  is  seen  as  a  whitish  cloudiness 
of  that  body.     In  one  of  Seely's  cases  recovery  occurred  under  quinine. 

Suppurative  choroiditis  is  described  in  one  case  by  Pennoff,  terminating  in 
destruction  of  the  eye. 

Paralysis  of  the  power  of  accommodation  has  been  noted  by  Bull  as  the 
result  of  malarial  infection,  and  spasm  of  the  accommodation  by  Stilling. 

The  Ear. — Certain  affections  of  the  ear  have  been  ascribed  to  malaria,  but 
only  a  few  can  be  regarded  as  really  due  to  the  malarial  infection.  Intermittent 
otalgia  occurs  as  an  expression  of  chronic  malarial  infection  and  is  relieved  in 
such  cases  by  quinine.  Frank,  Politzer,  and  De  Rossi  have  recorded  cases  of 
this  character;  intermittent  attacks  of  deafness  due  to  lesions  of  the  internal  ear 
or  the  auditory  nerve  brought  about  by  malarial  infection  have  been  reported  by 
Bar,  Wolff,  and  Ferreri,  but  there  is  always,  in  such  cases,  the  possibility  that 
18 


2J4       SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARIAL  FEVERS. 

the  deafness  was  really  due  to  quinine,  although  some  of  the  cases  described  by 
these  observers  were  undoubtedly  due  to  the  malarial  infection. 

Labyrinthine  vertigo  occurs  as  the  result  of  malarial  poisoning  and  has  been 
very  carefully  studied  by  Ferreri.  In  one  case  the  patient,  who  had  suffered 
from  slight  symptoms  of  aural  trouble  for  some  time,  had  an  attack  of  fever  and 
some  time  afterward  an  attack  of  deafness,  ringing  in  the  ears,  and  vertigo  of  so 
severe  a  type  that  he  fell;  this  was  followed  by  three  similar  attacks  and  the 
examination  of  his  blood  showed  the  presence  of  aestivo-autumnal  plasmodia. 
Treatment  with  quinine  cured  the  condition  in  two  months. 

The  cases  of  suppurative  otitis  media  mentioned  by  Liel,  Hotz,  and  De 
Rossi,  cannot  be  considered  as  due  to  malarial  infection,  for  the  malarial 
plasmodia  are  not  pyogenic  organisms  and  there  is  no  well  authenticated  in- 
stance upon  record  of  any  suppurative  process  due  to  these  parasites. 

The  special  senses  of  taste  and  smell  are  not  affected  by  malarial  infection. 

Miscellaneous  Sequelae. — Pigmentation  of  the  skin  is  a  very  common 
result  of  malarial  infection,  and  in  some  instances  is  so  marked  as  to  closely 
simulate  Addison's  disease.  It  is  probable  that  much  of  the  pigmentation  of 
the  skin  following  malaria  of  Europeans  in  the  tropics  is  as  much  due  to  the 
tropical  sunlight  as  to  the  malarial  infection,  for  it  is  a  common  experience 
to  observe  decided  pigmentation  of  the  skin  brought  about  by  residence  in  a 
tropical  country. 

Gangrene. — Fischer  and  Sarda  have  reported  severe  cases  of  dry  gangrene 
following  intense  malarial  infection,  but  such  a  condition  must  be  very  rare. 

The  changes  observed  in  the  subjects  of  malarial  cachexia  have  already 
been  considered. 

Postmalarial  Anaemia. — An  anaemia,  pernicious  in  character,  and 
presenting  the  same  blood  findings  as  are  found  in  cases  of  primary  pernicious 
anaemia,  occurs  very  rarely  as  a  sequela  of  malarial  infection.  I  have  observed 
but  one  such  case,  but  in  this  case  the  findings  in  the  blood  were  exactly  similar 
to  those  found  in  primary  pernicious  anaemia  and  I  believe  that  the  condition 
was  the  direct  result  of  malarial  infection. 

In  the  aestivo-autumnal  forms  of  malaria  the  anaemia  produced  by 
repeated  attacks  may  be  very  severe  and  very  persistent.  In  the  tertian  and 
quartan  fevers  the  regeneration  of  the  blood  is  very  rapid  as  compared  with  the 
aestivo-autumnal  fevers,  and  in  the  latter  the  number  of  red  blood-corpuscles 
may  reach  a  very  low  level.  I  remember  several  cases  in  which  the  number  of 
red  cells  was  not  over  900,000  per  cubic  millimeter,  and  one  in  which  the  blood- 
count  showed  but  497,000  red  corpuscles  per  cubic  millimeter.  I  have  already 
discussed  the  anaemia  following  the  malarial  infections,  especially  that  of 
pernicious  character,  and  will  not  reconsider  the  subject  here. 

In  reviewing  the  subject  of  the  sequelae  of  the  malarial  fevers  I  have  in- 
cluded only  those  sequelae  which  are  of  importance  and  which  occur  with 
enough  frequency  to  merit  description.  There  are  many  sequelae  which  have 
been  reported  from  time  to  time,  by  various  authors,  which  I  have  not  spoken 


SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARIAL  LEVERS.       2?5 
of,  partly  because  they  are  of  such  rare  occurrence  as  to  },,  rf 

fever,  it  does  not  ^  w  Si,  "dt  "to  thT  I  f*  ",  ^  °f  """^ 
careful  in  our  conclusions  reg^ng  the  elfe  fZ  "f  ™  ^  '"  "' 
ditions  following  the  malariaf  fevers  ^  ^  ^^"^  a"d  con" 


II 


CHAPTER  II. 

The  Complications  of  the  Malarial  Fevers. 

The  malarial  fevers  may  be  complicated  by  or  associated  with  many 
other  diseases,  and  in  some  instances  it  would  appear  that  the  malarial  infection 
is  responsible  for  certain  of  the  complications,  but  the  old  theory,  first  advocated 
by  Boudin,  that  all  malarial  complications  were  due  to  the  malarial  poison,  has 
long  since  been  abandoned.  The  malarial  plasmodia  are  not  the  cause  of  a 
lobar  or  bronchopneumonia  complicating  malaria  nor  of  a  typhoid  which  may 
be  coexistent  with  it;  in  each  case  the  complicating  disease  is  due  to  its  specific 
organism,  and  though  the  course  and  clinical  symptoms  of  either  disease  may  be 
more  or  less  altered  by  their  association,  yet  their  etiology  remains  unchanged. 
In  other  words,  there  is  no  such  thing  as  a  typical  lobar  pneumonia  due  alone  to 
the  malarial  plasmodia  or  a  peculiar  form  of  typhoid  fever  caused  by  these 
organisms. 

Of  the  many  diseases  which  may  complicate  the  various  forms  of  malaria, 
and  especially  the  aestivo-autumnal  infections  (for  these  infections,  being  more 
severe  in  character  than  the  tertian  and  quartan,  are  more  apt  to  be  accompanied 
by  complications),  the  following  may  be  mentioned: 

Complications  Observed  in  the  Nervous  System. — Coincident  with  the 
malarial  fevers  there  may  occur  attacks  of  acute  mania,  such  cases  having  been 
described  by  Yanarris,  but  this  complication  is  very  rare.  Hysteria  is  a  com- 
mon complication  in  nervous  women,  and  even  in  men,  and,  as  in  hysterical 
attacks  in  general,  the  symptoms  vary  greatly  in  character  and  severity. 
Paraplegia  and  hemiplegia  may  rarely  complicate  these  fevers,  and  neuroses  of 
various  kinds  are  not  uncommon.     Meningitis  may  occur  as  a  complication. 

Complications  Observed  in  the  Respiratory  System. — The  most  com- 
mon complication  observed  in  the  respiratory  system  is  acute  bronchitis.  A  mild 
form  of  this  affection  is  observed  in  very  many  cases  of  malaria,  probably  due 
to  the  infection  per  se,  but  not  infrequently  a  severe  form  of  bronchitis  will 
complicate  our  malarial  cases  and  may  persist  for  weeks  after  the  infection  has 
disappeared. 

Both  lobar  and  lobular  pneumonia  occur  as  complications  of  the  malarial 
fevers,  the  first  being  by  no  means  a  rare  complication.  Early  observers  held 
that  the  pneumonia  sometimes  accompanying  malaria  was  directly  due  to  the 
malarial  plasmodia,  but  recent  investigations  have  conclusively  shown  that  these 
organisms  are  unable  to  produce  a  true  pneumonitis.  The  pneumonic  symp- 
toms which  appear  in  certain  cases  are  undoubtedly  due  to  the  localization  of 
the  plasmodia  in  the  lungs,  and  I  have  already  described  the  form  of  pernicious 

276 


SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARIAL  FEVERS.       277 

malaria  in  which  the  symptoms  are  chiefly  referred  to  the  lung  and  are  practi- 
cally identical  with  those  of  lobar  pneumonia,  but  a  microscopical  exami- 
nation of  sections  of  the  lung  in  such  cases  shows  that  the  lesions  present  differ 
considerably  from  typical  of  lobar  pneumonia. 

Lobar  pneumonia  may  complicate  the  malarial  fevers  at  any  time,  and  may 
develop  suddenly  or  insidiously.  In  some  instances  the  course  of  the  disease 
is  similar  to  that  in  a  patient  in  whom  no  malarial  infection  is  present,  while 
in  others,  the  course  of  the  pneumonia  is  interrupted  by  chills  and  exacerbations 
of  fever  due  to  the  malarial  infection.  The  pneumonic  symptoms  may  mask 
the  malaria,  or  vice  versa.  The  prognosis  in  pneumonia  complicating  the 
aestivo-autumnal  fevers  is  very  grave,  Ascoli  placing  the  mortality  as  high  as 
60  to  78  per  cent,  in  patients  who  have  suffered  from  repeated  attacks  of  malaria. 
Death  may  occur  from  thirty-six  to  seventy-two  hours  from  the  initiation  of  the 
pneumonic  symptoms. 

Broncho-pneumonia  or  lobular  pneumonia  occurs  as  a  complication  less 
frequently  than  lobar  pneumonia  and  resembles  in  its  pathology  the  form 
produced  by  the  plasmodia  more  closely  than  does  lobar  pneumonia.  Clini- 
cally, the  two  conditions  (typical  lobular  pneumonia  and  the  form  produced  by 
the  plasmodia)  cannot  be  distinguished. 

In  cases  of  pneumonia  complicating  malaria  which  recover,  the  convales- 
cence is  generally  verj  slow,  resolution  being  greatly  delayed.  An  empyema 
may  result  in  rare  instances.  Not  rarely  the  affected  portions  of  the  lung  become 
fibroid,  and  a  chronic  fibroid  pneumonia  results,  or  bronchiectasis  may  occur. 

Pneumonic  septicaemia  has  been  described  by  Bignami,  Marchiafava, 
and  Nazari  as  complicating  malaria.  This  condition  appears  in  patients 
suffering  from  long-continued  malarial  infection  who  have  developed  pneumonia, 
and  has  only  been  observed  in  aestivo-autumnal  infections. 

In  malarial  patients  in  whom  pneumonia  has  occurred  as  a  complication, 
the  latter  disease  is  very  apt  to  terminate  in  delayed  resolution;  a  typhoid  state, 
followed  by  death;  pneumococcic  septicaemia  or  induration.  All  of  these 
terminations  are  frequent  in  patients  who  present  the  symptoms  of  malarial 
cachexia. 

Pleurisy  has  been  reported  by  Hertz  as  a  complication  of  the  malarial  fevers, 
but  it  is  a  very  rare  one. 

Tuberculosis. — The  old  belief  that  tuberculosis  and  malaria  were 
antagonistic  and  that  they  seldom  occurred  together  has  been  proven  false,  and 
we  now  know  that  both  diseases  are  very  commonly  associated  and  that  fatal 
cases  of  malaria  may  occur  in  patients  suffering  from  tuberculosis.  Marchia- 
fava claims  that  "if  the  malarial  infection  attacks  organisms  affected  by 
tuberculosis,  the  latter  is  not  arrested,  but  acquires  a  tendency  to  spread,  and 
produces  miliary  tuberculosis."  This  statement  is  interesting  and  in  my 
experience  true,  for  I  have  repeatedly  observed  miliary  tuberculosis  in  malarial 
subjects,  and  the  number  of  instances  of  miliary  tuberculosis  discovered  at 
autopsy  in  patients  who  were  also  the  victims  of  severe  malarial  infections,  has, 


278       SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARLA.L  FEVERS. 

in  my  experience,  been  remarkable.  I  have  repeatedly  seen  cases  diagnosed  as 
pulmonary  tuberculosis  in  which  there  were  physical  signs  of  cavity  formation 
and  consolidation,  and  which  later  developed  severe  malarial  infection.  At 
autopsy,  besides  the  presence  of  cavities  and  large  areas  of  consolidation,  a 
severe  miliary  tuberculosis  was  found,  thus  proving,  I  believe,  the  truth  of 
Marchiafava's  contention,  that  malarial  infection  in  the  subjects  of  tuberculosis 
stimulates  the  formation  of  miliary  tubercles.  The  same  authority  claims 
that,  unlike  other  cachexias,  malarial  cachexia  does  not  predispose  to  tubercu- 
losis. In  view  of  the  effect  of  malarial  infection  upon  existing  tuberculosis,  it 
is  obvious  that  such  infection  should  be  promptly  recognized  and  eliminated. 

If  quinine  be  administered  to  a  patient  suffering  from  any  of  the  compli- 
cations mentioned,  it  will  be  followed  by  the  cessation  of  the  malarial  symptoms, 
and  the  complicating  process  will  run  its  usual  course. 

Complications  Observed  in  the  Circulatory  System. — Any  of  the 
organic  diseases  of  the  heart  may  complicate  a  malarial  infection,  and  in  severe 
aestivo-autumnal  infections  the  prognosis  may  be  exceedingly  grave.  Acute 
endocarditis  may  occur  as  a  complication,  but  is  never  due  to  malarial  infections, 
as  has  been  claimed  by  Lancereaux.  The  ulcerative  form  of  endocarditis  may 
occur  following  a  pneumonic  complication.  A  systolic  murmur  is  often  present 
in  severe  malarial  infections,  and  functional  disorders  are  very  common.  A 
slow  pulse  during  convalescence  is  very  frequently  observed,  sometimes  counting 
but  forty  beats  to  the  minute. 

Complications  Observed  in  the  Genito-urinary  System. — The  most 
common  complication  observed  in  the  genito-urinary  system  isnepJiritis.  While 
albuminuria  is  very  common,  it  can  hardly  be  called  a  complication,  as  it  is  un- 
doubtedly due  to  the  malarial  infection  and  is  so  common  as  to  constitute  a 
symptom  of  the  disease.  Thus  Thayer,  in  691  cases  of  malaria,  found  albu- 
minuria in  321  instances,  or  46.4  per  cent.  In  my  own  experience  I  have  found 
albuminuria  in  at  least  50  per  cent,  of  all  cases.  It  is  most  frequently  observed 
in  aestivo-autumnal  infections;  thus  Thayer  found  that  in  tertian  and  quartan 
infections  it  occurred  in  38.6  per  cent,  of  all  cases,  while  in  aestivo-autumnal 
infections  it  occurred  in  58.3  per  cent,  of  all  cases.  My  own  figures  confirm 
those  of  Thayer  as  regards  tertian  and  quartan  infections,  but  I  have  found 
that  at  least  65  per  cent,  of  aestivo-autumnal  infections  show  albumin  in  the 
urine  and  that  the  condition  is  always  present  in  fatal  malarial  infections. 

Some  form  of  nephritis  occurred  as  a  complication  in  at  least  4  per  cent,  of 
the  aestivo-autumnal  cases  I  have  observed,  and  in  one-half  of  1  per  cent,  of 
tertian  and  quartan  infections.  Very  often  the  nephritis  is  an  acute  one,  due 
directly  to  the  malarial  infection,  as  is  proven  by  the  disappearance  of  the  condi- 
tion after  the  cessation  of  the  malarial  attack,  but  not  infrequently  a  chronic  or 
subacute  nephritis,  already  existing,  complicates  the  malarial  infection,  and  in 
such  cases  the  prognosis  is  often  grave.  Thayer  states  that  among  1,832  cases 
of  malarial  fever  observed  at  the  Johns  Hopkins  Hospital,  acute  nephritis  was 
present  in  26  instances,  in  all  but  three  instances  undoubtedly  due  to  the  ma- 


SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARIAL  FEVERS.       279 

larial  infection.  Of  these  cases  four  died,  one  from  the  malaria]  infection,  the 
others  as  the  result  of  the  nephritis.  It  will  thus  be  seen  that  this  complication 
is  sometimes  a  fatal  one  and  that  in  the  majority  of  instances  it  is  caused  by  the 
malarial  infection.  A  further  discussion  of  nephritis  as  a  result  of  malarial 
infection  will  be  found  in  the  chapter  dealing  with  the  sequelae  of  the  malarial 
fevers. 

Orchitis  and  epididymitis  may  occur  as  complications  of  the  malarial  fevers, 
but  a  history  of  gonorrhoea  is  usually  to  be  obtained.  These  complications  are 
especially  common  among  soldiers,  and  neither  condition  appears  to  be  ag- 
gravated by  the  malarial  plasmodia.  In  some  cases  of  epididymitis  the  tem- 
perature chart  is  rendered  atypical  because  of  the  fever  accompanying  the 
genital  condition.  The  cases  of  orchitis  described  by  Maural,  Calmette, 
Schmidt,  and  others  are  open  to  serious  question,  as  being  due  to  malarial 
infection,  although  very  rarely  such  a  condition  may  occur. 

Gangrene  of  the  penis,  the  scrotum,  and  the  labia  has  been  described  by 
Mannaberg  as  complicating  or  following  malarial  infection.  These  conditions 
might  easily  occur  as  complications,  but  I  believe  that  it  is  very  doubtful  if  they 
occurred  as  the  result  of  malarial  infection. 

Complications  Observed  in  the  Gastrointestinal  Tract. — The  most 
frequent  and  important  disease  of  the  gastrointestinal  tract  complicating 
malaria  is  dysentery,  either  amoebic  or  specific,  or  some  form  of  enteritis.  In 
patients  returning  to  temperate  regions  from  the  tropics  where  either  specific  or 
amoebic  dysentery  is  epidemic  or  endemic,  it  is  very  common  to  observe  the 
coexistence  of  these  diseases  with  malaria.  In  the  case  of  soldiers  returning 
from  the  Philippine  Islands,  as  observed  at  the  U.  S.  Army  General  Hospital 
at  San  Francisco,  over  65  per  cent,  showing  malarial  plasmodia  were  also 
suffering  from  either  chronic  specific  dysentery  or  amoebic  dysentery.  Of  these 
cases  25  per  cent,  were  suffering  from  amoebic  dysentery,  as  shown  by  the 
presence  of  Entamoeba  histolytica  in  the  faeces.  The  combination  of  these  two 
protozoan  infections,  malaria  and  amoebic  dysentery,  is  very  common  in  the 
Philippine  Islands,  and  the  malarial  infection  appears  to  aggravate  the  dysen- 
teric condition.  When  malaria  is  complicated  by  dysentery,  or  vice  versa,  the 
dysenteric  symptoms  are  aggravated,  and  the  prognosis  is  much  worse  than 
when  either  disease  occurs  alone.  The  symptoms  of  malaria  are  often  masked 
by  those  of  dysentery,  or  the  malarial  infection  may  be  latent.  The  administra- 
tion of  quinine  in  patients  suffering  from  malaria  complicated  by  dysentery,  not 
only  removes  the  malarial  infection,  but,  in  the  majority  of  instances,  markedly 
benefits  the  dysentery  condition,  and  a  return  to  health  is  more  rapid.  The 
explanation  of  this  fact  is  not  hard  to  find.  We  know  from  pathological  studies 
that  the  mucous  membrane  of  the  intestine  is  generally  invaded  by  the  malarial 
plasmodia,  which  invasion  must  necessarily  injure  the  vitality  of  the  tissues; 
removal  of  the  plasmodia  by  quinine  aids  the  tissues  in  regaining  their  normal 
vitality,  and  thus  indirectly  improves  the  dysenteric  condition. 

In  a  certain  proportion  of  patients  suffering  from  malarial  infection  in 


280       SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARLA.L  FEVERS. 

which  dysenteric  symptoms  are  present,  the  latter  symptoms  are  undoubtedly 
due  to  the  localization  of  the  plasmodia  within  the  capillaries  of  the  intestine, 
as  I  have  already  shown,  and  in  such  patients  the  administration  of  quinine 
is  rapidly  followed  by  complete  recovery. 

Typhoid  Fever. — The  complication  of  malarial  infection  by  typhoid 
fever  is  a  most  important  and  interesting  one,  which  will  be  fully  considered  in 
the  following  chapter. 

Cholera  may  complicate  malaria,  and  such  instances  have  been  described 
by  Bastianelli  and  Sternberg.  I  have  autopsied  several  Filipinos  who  had 
died  of  cholera  in  whom  the  spleen  showed  evidence  of  malarial  infection,  but  I 
have  never  observed  a  case  clinically  in  which  cholera  and  malaria  coexisted. 
There  is  no  reason  to  doubt,  however,  that  cholera  complicates  malaria  fre- 
quently during  widespread  cholera  epidemics. 

Acute  Infections  Complicating  Malaria. — Almost  all  of  the  acute 
infectious  diseases  have  been  reported  as  complicating  malaria.  Smallpox, 
measles,  diphtheria,  Malta  fever,  erysipelas,  acute  articular  rheumatism,  and 
streptococcic  septicaemia  have  all  been  observed  during  malarial  attacks,  and  it 
is  probable  that  such  cases  occur  much  more  frequently  than  we  have  supposed 
in  regions  in  which  malaria  is  prevalent. 

Miscellaneous. — To  Sternberg  and  to  Kelsch  and  Kiener  we  owe  the 
knowledge  that  insolation  is  a  frequent  complication  of  the  malarial  fevers, 
and  that  it  often  aids  in  the  production  of  a  pernicious  attack.  Exposure  to 
the  sun's  rays  in  a  person  debilitated  by  repeated  malarial  paroxysms  is  very  apt 
to  be  followed  by  sunstroke,  and  it  is  well  known  that  such  exposure  is  very 
efficient  in  bringing  out  the  symptoms  of  malaria  in  cases  in  which  the  infection 
is  latent.  I  have  often  observed  that  a  drill  in  the  tropics  is  followed  by  the 
admission  to  the  military  hospital  of  many  cases  suffering  from  malaria,  develop- 
ing, in  those  so  exposed,  during  or  immediately  after  the  drill,  and  in  m\  ex- 
perience more  than  one  pernicious  attack  of  malaria  was  preceded  by  pro- 
longed exposure  to  the  rays  of  the  tropical  sun.  It  is  now  generally  admitted 
that  an  individual  who  has  suffered  from  repeated  attacks  of  malaria  is  much 
more  sensitive  to  the  sun's  rays  than  one  who  has  not,  and  that  insolation  is  very 
apt  to  occur  in  such  cases. 

Puerperal  women  who  have  suffered  from  attacks  of  malaria  are  more 
liable  to  complications,  such  as  puerperal  fever,  hemorrhages,  and  abortion,  than 
are  those  free  from  such  infection,  because  of  the  anaemia  invariably  present, 
and  the  lowered  vitality  of  the  tissues.  Abortion  complicates  malarial  infection 
frequently  in  regions  where  the  aestivo-autumnal  fevers  are  prevalent,  and  it 
has  long  been  known  that  abortion  is  much  more  frequent  in  malarial  countries 
than  in  others.  Thus  Weatherley,  who  has  given  this  subject  careful  study, 
found  that  in  the  East  Indies  as  many  as  46.6  per  cent,  of  pregnant  women 
aborted,  while  in  England  only  3.56  per  cent,  aborted.  Of  course  these  figures 
are  likely  to  be  only  approximate,  but  they  demonstrate  the  fact  that  in  malarial 
regions  abortion  occurs  much  more  frequently  than  in  immune  localities. 


SEQUELAE,  CONPLICATIONS,  AND  PROGNOSIS  OF  MALARIAL  FEVERS.       281 

In  the  tropics  the  malarial  infections  may  be  complicated  by  infe<  tion 
with  any  of  the  animal  parasites  so  commonly  found  in  such  regions.  A 
combined  infection  of  malaria  and  Anchylostoma  duodenalis  or  Necator  ameri- 
canns  is  frequently  observed,  and  is  always  a  serious  condition,  as  both  parasites 
produce  anaemia.  Combined  infections  of  malaria  and  fdariasis  have  been 
reported  several  times  and  are  probably  of  a  very  common  occurrence  in  regions 
where  filariasis  is  prevalent.  Infections  with  Schistosoma  haematobium  and 
Paragonimus  westermanii  sometimes  complicate  the  malarial  fevers  and  greatly 
delay  recovery  from  the  malarial  infection.  I  have  already  discussed  the 
frequent  association  of  the  malarial  plasmodia  and  Entamoeba  histolytica  and 
called  attention  to  the  importance  of  recognizing  this  complication. 

Of  other  diseases  which  may  complicate  the  malarial  fevers  may  be  men- 
tioned diabetes  mellitus,  sciatica,  tonsillitis,  parotitis,  and  various  skin  diseases. 
Any  of  the  chronic  diseases  affecting  the  viscera  may  complicate  the  malarial 
fevers  and  in  many  instances  render  the  prognosis  very  grave. 

Malaria  as  a  Puerperal  and  Postoperative  Complication. — A  malarial 
paroxysm  often  follows  parturition  in  women  who  have  become  infected,  and 
pernicious  symptoms  may  develop  in  such  cases  unless  the  infection  is  promptly 
treated.  It  is  also  well  known  that  a  latent  malarial  infection  is  often  made 
manifest  by  an  operation  or  by  trauma,  and  in  malarial  regions  many  post- 
operative fevers  are  malarial  even  though  quinine  may  have  been  administered 
in  small  doses  as  a  prophylactic.  In  fevers  arising  during  the  puerperium  and 
following  wounds  and  operations  it  should  always  be  remembered  that  a  micro- 
scopical examination  of  the  blood  is  indicated,  especially  in  malarial  regions  or 
in  patients  who  have  resided  in  such  localities;  such  an  examination  will  often 
remove  a  load  of  anxiety  from  the  mind  of  the  obstetrician  or  surgeon,  and 
frequently  result  in  the  saving  of  the  life  of  the  patient. 

Literature   upon   the  Sequelae  and   Complications   of  the  Malarial   Fevers. 

1856.  Morehead.     Clinical  Researches  on  Diseases  in  India.     London. 

1857.  Griesinger.     Infections  Krankheiten.      Virchow's  Handbuch  der  spec. 
Path.  u.  Therapie. 

1868.     Jacobi.      Zwei    verschiedene    Falle    von     Neuritis    optica.      Archiv.    f. 

Opthal.,  14,  p.  149. 
1875.      B  artels.      Krankheiten     des     Harnapparates.      Ziemssens     Handbuch 
der  spec.     Path.,  vol.  ix. 

1877.  Bull.      American  Journal  Medical  Sciences,  p.  413. 

1878.  Poncet.      Retino  choroidite  palustre.      Annal.   oculistique,   Maj^. 

1879.  Bodnar.      Ueber    Bubo    malaricus.     Pester   med-chir.    Presse,    No.    47 
1879.      Levrier.      Accidents  oculaires  dans  les  fievres  intermittentes.      Thesis 

d.  Paris. 
1879.      Kahler  and  Pick.      Beitrage  zur  Pathologie  und  pathol.    Anatomie  des 

Centralnervensystem.      Leipzig,   p.    61. 
1882.      Fayrer.      On  the  Climate  and  Fevers  of  India.      London. 
1882.      Kelsch  and  Kiener.      Les  alterations  paludeennes  des  reins.      Archiv. 

de  Physiologie  normale  et  pathologique. 


282   SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARIAL  FEVERS. 

1883.      Maurel.      Traite  des  maladies  paludeennes  a  la  Guyane.      Paris. 

1885.  Seely.      A  Second  Case  of  Serous  Effusion  into  the  Vitreous  Humor,  etc., 
Proc.  Amer.  Oph.  Society. 

1SS6.     Petit   and   Verneuil.     Asphyxie  locale  et  gangrene  palustres.      Rev. 
de  chirurgie,  No.  3. 

1886.  Hertz.      Malariainfectionen.    Ziemssen's  Handbuch.  d.  spec.      Pathologie 
u.  Therapie,  Leipzig. 

18S6.      Schmidt.     Observations    d'orchite    paiudeenne.     Arehiv.     de    med.     et 

pharm.   Mil.,'  No.  S. 
18S6.      Rosenstein.      Pathologie    und    Therapie     der     Nieren-krankheiten,    3d. 

Ed.,  Berlin. 
1886.     Segard.      Rapport   medical  de  la  Creuse  a  Madagascar.     Arch.  d.  med. 

navale,   46,   p.    5. 

1886.  Berthelon.      Orchites   paludeennes   primitives.      Arch,    de   med.    et   de 
phar.,  mil.,  October. 

1887.  Berthelon.     Ann.    des  mal.   org.   gen.-urin.,  p.  312. 

1887.      Charvot.      Etude  clinique  sur  l'orchite  paiudeenne.      Bull,  et  mem.  de  la 

Soc.   de   chir.,   p.    597. 
1887.      Magnin.      Sull'   orchite   d'origine  palustre.      Gaz.   med.    Ital.   Lombard, 

No.  42. 

1887.  Canalis.      Etude  sur  un  cas  de  sclerose  en  plaques,  etc.  Gaz.  hebd.  de 
Med.,  p.  554. 

1888.  Sacchi.      Sulla  paralisi  da  malaria.  Neurol.  Centralbl.  No.  7,  p.  634. 
18S9.      Kipp.     Further  Observations  of  Malarial  Keratitis.      N.  Y.  Med.  Record, 

August. 

1889.  Martin.      Aerztliche    Erfahrungen  iiber   die   Malaria   der  Tropenlander, 
Berlin. 

1889.     Fassina.      Des  abces  de  la  rate  dans  les  maladies  infectieuses,  etc.,  Thesis 
de  Paris,  No.  230. 

1889.  Kelsch  and  Kiener.      Maladies  des  pays  chauds.     Paris. 

1890.  MacNamara.      Malarial  Neuritis  and  Neuroretinitis.      Brit.  Med.  Jour., 
P-  54o. 

1890.      Schellong.      Die  Malaria  Kranheiten  in  Kaiser  Wilhelms  Land.      Berlin 

1890.  Sulser.      Klin.  Monatsblatter  fur  Augenheilkunde. 

1891.  Lancereaux.      Du  Paludisme.      Bull,     med.,  p.  959. 

1 89 1.  Marchiafava    and    Bignami.      Malaria.     Twentieth   Century   Practice, 
vol.  xix,  New  York. 

1892.  Torti    and    Angelini.      Infezione    malarica    cronica    coi    sintorni    della 
sclerosi  a  plache.      Bull,   della  Soc.      Lancisiana. 

1892.      Raynaud.     Troubles  oculaires  de  la  malairia.     Thesis  de  Paris,  No.  166. 
1894.      Boinet  and  Salabert.      Les  troubles  moteurs  dans  1'impaludisme.      IX 

Internat  Med.  Congress.  Rome,  vol.  iii,  p.  82. 
1896.  Vallin.  Bull,  de  l'acad.  d.  med.,  xxxv,  p.  366. 
1896.      Metin.      Un  cas.   de  polynevrite  d'origine  paiudeenne.      Arch.    d.   med. 

navale,    No.    66. 
1896.      Grocco.      A    Proposito    dell'    emoglobinuria    da    chinina    nei    malarici. 

Arehiv.   ital.   di   clin.   med.,   p.    716. 

1896.  Senator.      Erkrankungen  der  Nieren.      Nothnagles  Treatise.      Vienna. 

1897.  Pasminik.      Ueber     Malariapsychosen.      Wiener     med.      Wochenschrift, 

P-  5*7- 

1898.  Thayer.      On  Nephritis  of  Malarial  Origin.     Trans.  Assoc.   Am.  Phys. 

1899.  Edmonds.      Malaria  and  Pregnancy.      Brit.  Med.  Jour.,  Apr.  29,  p,  1023. 


SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARIAL  FEVERS.       283 

1902.      Daniels.      Notes  on  Malaria  and  Other  Tropical  Diseases.      Brit.  Guinea 

Med.  Ann.,  No.  1,  p.  40. 
1902.      Bernheim.      Tuberculose  et  paludisme.      Rev.  internationale  de  la  tuber- 

culose,  p.  894. 

1902.  Davidson.      Carcinoma  and  Malaria.      Brit.  Med.  Jour.,  vol.  i,  p.  77. 

1903.  Moore,  J.  T.  Postoperative  Malaria,  etc.,  N.  Y.  Med.  Record,  vol.  lxiii, 
p.  291. 

1905.  Tsuzuki.  Ueber  die  Sekundare  Infektion  mit  Frankelschen  Pneumo- 
kokken  bei  Malariakranken.  (Malariapneumonie.)  Archiv.  f.  Schiffs-  u. 
Tropen-Hyg.,  Bd.  ix,  p.  442. 

T905.      Mannaberg.      Malaria.      Nothnagel's  Practice.      English  Trans,      Phil. 

1907.     Craig,  C.    F.     The  Malarial  Fevers,  in  Osier's  "Modern  Medicine," 
vol.  i,  Philadelphia. 


CHAPTER  III. 

Coincident  Typhoid  and  Malarial  Infection. 

The  simultaneous  occurrence  of  typhoid  and  malarial  fever  is  a  subject 
of  much  interest  to  investigators,  and  one  which  has  given  rise  to  much  contro- 
versy, and  has  evoked  many  varying  opinions  from  eminent  authorities.  Dur- 
ing the  war  of  the  Rebellion  a  great  number  of  cases  of  fever  were  observed 
which  did  not  answer  to  the  typical  characteristics  of  either  typhoid  fever  or  the 
malarial  fevers,  and  Woodward,  a  Major  Surgeon  of  the  Union  Army,  designated 
such  fevers  as  "typho-malarial"  fever,  a  classification  accepted  by  the  Army 
authorities.  From  July  i,  1862,  until  June  30,  1866,  there  were  reported  to  the 
Surgeon-General's  office  57,400  cases  of  typho-malarial  fever,  with  5,360 
deaths.  Woodward,  in  thus  designating  these  fevers,  never  intended  that  the 
name"should  indicate  a  disease  entity,  but  a  hybrid  condition,  brought  about  by 
the  combination  of  typhoid  and  malarial  infection,  and  differing  clinically 
from  either  of  these  diseases.  Thus,  in  a  paper  read  before  the  International 
Medical  Congress  at  Philadelphia,  in  1876,  he  stated: 

"I  never  meant  this  term  (typho-malaria)  to  represent  a  specific  type  of 
fever,  but  intended  it  to  designate  all  the  many-faced  brood  of  hybrid  forms 
resulting  from  the  combined  influence  of  the  causes  of  malarial  fever  and  of  enteric 
fever." 

Again. he  says: 

"And  this  brings  me  at  length  to  answer  the  question,  Is  typho-malarial 
fever  a  special  type  of  fever?  and  I  reply  unhestitatingly  that  it  is  not.  I,  at 
least,  am  free  from  the  blame  of  that  error,  if  anyone  has  fallen  into  it." 

Unfortunately,  many  practitioners  did  fall  into  the  error  of  regarding 
typho-malarial  fever  as  a  distinct  disease  and  the  term  soon  became  of  common 
diagnostic  use,  and  was  the  cause  of  great  confusion  in  the  study  of  the  con- 
tinued fevers.  Too  often  it  was  employed  to  cover  ignorance  of  the  condition 
present  and  even  to-day  a  diagnosis  of  typho-malarial  fever  is  not  infrequently 
made  in  long-continued  fevers  in  which  uncertainty  exists  as  to  the  exact  nature 
of  the  infection.  For  this  reason  the  term  should  be  abandoned,  for  research 
has  demonstrated  that  while  typhoid  fever  may  be  complicated  by  malaria,  and 
vice  versa,  there  is  no  reason  for  applying  a  special  name  to  the  combination, 
and  clinically  the  cases  do  not  present  any  characteristic  group  of  symptoms. 

While  a  great  number  of  coincident  infections  with  typhoid  and  malarial 
fever  have  been  reported  in  the  literature  of  medicine,  very  few  have  been 
studied  scientifically,  and  since  the  discovery  of  the  plasmodia  of  malaria  and 

284 


SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARIAL  FEVERS.       285 

the  Widal  test  there  have  been  but  a  small  number  of  cases  reported  in  which 
the  diagnosis  was  rendered  certain  by  the  use  of  laboratory  methods. 

Historical. — Prior  to  the  use  of  the  Widal  test  in  the  diagnosis  of  typhoid 
fever  numerous  observers  had  reported  cases  in  which  the  malarial  plasmodia 
were  found  in  the  blood  and  in  which,  after  the  disappearance  of  these  organisms, 
the  fever  persisted  and  presented  the  symptoms  of  typhoid.  Laveran  was 
probably  the  first  to  mention  such  cases,  describing  two,  in  one  of  which  inter- 
mittent fever  occurred  during  convalescence  from  typhoid,  and  another  in  which 
the  malarial  fever  preceded  and  followed  the  typhoid.  Kinyoun  described 
several  cases  in  1899,  dividing  them  into  those  in  which  the  malarial  symptoms 
predominated  and  those  in  which  the  symptoms  of  typhoid  were  most  prominent. 
Other  cases  have  been  reported  by  Thompson,  Osier,  and  Vincent.  While 
most  of  these  cases  were  undoubtedly  instances  of  coincident  typhoid  and 
malarial  infection,  and  the  malarial  plasmodia  were  demonstrated  in  the  blood 
of  the  patients,  in  none  of  them  was  the  Widal  test  applied,  nor  were  the  typhoid 
bacilli  separated  from  the  excreta,  so  that  an  element  of  doubt  exists  regarding 
some  of  the  cases. 

The  only  cases  in  which  we  can  be  sure  that  such  a  coincident  infection 
occurs  are  those  in  which  one  of  the  malarial  plasmodia  can  be  demonstrated 
in  the  blood,  and  at  the  same  time  some  substantial  proof  of  the  existence  of 
typhoid,  as  the  separation  of  the  bacilli  from  the  blood,  rose  spots,  or  excreta,  or 
a  positive  reaction  to  the  Widal  test,  can  be  shown  to  exist.  Applying  such  tests 
the  number  of  cases  of  coincident  typhoid  and  malarial  infection  which  have 
been  reported  are  surprisingly  few,  and  I  believe  that  while  the  combination  of 
these  diseases  is  much  more  common  than  the  number  of  cases  reported  would 
lead  us  to  believe,  still  the  condition  is  a  rare  one  when  we  consider  the  chances 
of  such  infections  in  localities  in  which  both  diseases  are  prevalent. 

Frequency  of  Occurrence. — The  researches  of  Lyons  and  of  Reed, 
Vaughn,  and  Shakespeare  prove  that  coincident  typhoid  and  malarial  infection 
is  of  rare  occurrence.  Lyons,  in  1900,  collected  all  of  the  cases  of  coincident 
typhoid  and  malaria  on  record  in  which  the  plasmodia  were  found  in  the  blood 
and  sufficient  proof  existed  that  typhoid  fever  was  present,  and  found  that 
they  only  numbered  29  in  all.  In  the  classical  report  upon  the  "Spread  of 
Typhoid  Fever  in  the  United  States  Military  Camps  during  the  Spanish  War 
of  1898"  by  Reed,  Vaughn,  and  Shakespeare,  which  included  data  up  to  1904, 
there  are  collected  95  cases  in  which  these  diseases  coexisted,  but  only  12  are 
reported  as  occurring  during  the  active  stage  of  the  typhoid  fever.  Curry,  who 
examined  the  blood  of  hundreds  of  cases  of  typhoid  during  the  same  war  found 
only  one  case  in  which  malaria  occurred  during  the  active  symptoms  of  typhoid, 
and  Ewing,  at  Montauk  Point,  observed  no  case  in  which  such  infection  occurred, 
although  he  saw  many  cases  of  typhoid  develop  malaria  during  convalescence. 
As  the  result  of  his  observations  he  concludes  that  typhoid  and  malaria  are 
incompatible,  the  malarial  symptoms  apparently  being  held  in  abeyance  by 
the  coexisting  typhoid  infection.     Da  Costa  reports  three  cases  of  coexistent 


286       SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARLAL  FEVERS. 

typhoid  and  malaria,  Muehleck,  live  cases,  and  Witherington,  three  cases  in 
which  the  malaria  was  coincident  with  the  active  symptoms  of  typhoid. 

In  my  own  experience,  covering  the  observation  of  hundreds  of  cases  of 
typhoid  fever,  and  thousands  of  malarial  infection,  I  have  seen  but  ten  instances 
of  coincident  typhoid  and  malarial  infection.  It  should  be  understood  that 
I  regard  as  coincident  infections  only  those  in  which  the  malarial  paroxysms 
occur  during  the  active  symptoms  of  typhoid  and  not  during  convalescence. 
It  is  not  at  all  uncommon  to  observe  the  occurrence  of  malarial  paroxysms 
during  convalescence  from  typhoid  or  preceding  that  disease,  but  such  instances 
cannot  be  considered  as  true  examples  of  coincident  infection. 

From  the  data  given  it  is  evident  that  coincident  infections  with  typhoid 
and  malaria  are  rare,  and  that  while  cases  do  occur,  their  number  is  insignificant 
when  compared  to  the  number  of  cases  of  typhoid  and  malaria  observed  in  the 
endemic  areas  of  these  diseases.  There  is,  I  believe,  good  reason  for  think- 
ing that  there  does  exist  a  certain  amount  of  incompatibility  between  the  two 
infections,  for  it  is  frequently  observed  that  when  typhoid  develops  in  a  patient 
suffering  from  malarial  fever,  the  malarial  symptoms  disappear,  as  well  as  the 
Plasmodia  from  the  peripheral  blood,  and  only  reappear  during  convalescence 
from  the  typhoid. 

Species  of  Malarial  Plasmodium  Present. — Any  of  the  species  of 
malarial  plasmodia  may  be  present  in  coincident  typhoid  and  malarial  infection, 
but  Plasmodium  vivax  has  been  most  frequently  observed.  In  44  cases  collected 
by  Reed,  Vaughn,  and  Shakespeare,  the  tertian  plasmodium  occurred  in  22 
the  aestivo-autumnal  in  12,  the  tertian  and  aestivo-autumnal  in  9,  and  the 
quartan  in  one,  a  case  reported  by  the  writer.  In  the  10  cases  observed  by 
myself,  six  were  infected  with  the  tertian  aestivo-autumnal  plasmodium,  three 
with  the  tertian  plasmodium,  and  one  with  the  quartan  plasmodium. 

Symptomatology. — It  may  be  stated  that  there  are  no  characteristic 
symptoms  of  coincident  malarial  and  typhoid  infection,  every  case  differing 
somewhat  in  this  respect.  The  occurrence  of  the  malarial  complication  is 
generally  evidenced  by  a  chill,  but  in  the  aestivo-autumnal  infections  the  chill 
may  be  absent,  the  patient  complaining  only  of  slight  chilly  sensations.  The 
fever  may  show  a  sudden  exacerbation  and  in  some  instances  every  malarial 
paroxysm  may  be  clearly  seen  upon  the  temperature  chart,  owing  to  the  sudden 
rise  in  the  temperature  curve.  This  is  beautifully  illustrated  in  the  chart  given 
of  coincident  typhoid  and  quartan  malaria  and  also  in  that  illustrating  a 
coincident  typhoid  and  aestivo-autumnal  infection.  Paroxysms-of  chill,  fever, 
and  sweating,  occurring  during  an  attack  of  typhoid  are  very  significant  of  a 
malarial  complication,  but  such  paroxysms  occur  in  typhod  from  other  causes, 
and  we  cannot,  therefore,  base  our  diagnosis  upon  them.  The  abdominal 
symptoms  are  generally  increased  during  the  malarial  infection,  and  this  is 
also  true  of  the  symptoms  connected  with  the  nervous  system.  The  headache 
is  very  severe  and  delirium  is  almost  invariable  present,  even  in  those  cases 
in  which  it  was  absent  befpre  the  appearance  of  the  malarial  paroxysm.     In 


SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARIAL  FEVERS.       287 

general,  it  may  be  stated  that  all  the  symptoms  of  typhoid  are  increased  in 
severity  and  there  are  added  to  them  the  symptoms  commonly  observed  in  a 
malarial  paroxysm. 

When  malaria  occurs  during  convalescence  from  typhoid  it  is  generally 
manifested  by  chills,  fever,  and  sweats,  and  the  temperature  curve  is  charac- 
teristic of  the  type  of  malaria  which  may  be  present.  It  should  be  remembered, 
however,  that  paroxysms  of  chill,  fever  and  sweating  are  sometimes  observed 
at  the  onset  of  typhoid  and  during  convalescence  from  that  disease,  so  that  the 
occurrence  of  such  paroxysms  does  not  always  mean  the  presence  of  a  malarial 
infection. 

The  effort  which  has  been  made  to  ascribe  to  cases  of  so-called  "typho- 
malarial  fever"  a  more  or  less  definite  and  characteristic  symptomatology  has 
resulted  in  failure,  and  the  most  that  we  can  say  as  to  the  symptomatology 
of  these  coincident  infections  is  that  the  symptoms  present  are  those  commonly 
present  in  both  diseases,  but  in  these  cases  combined,  thus  giving  rise  to 
atypical  clinical  pictures,  in  which  sometimes  the  typhoid  symptoms  predomi- 
nate and  sometimes  those  of  the  malarial  infection. 

Illustrative  Cases. — The  following  cases  of  coincident  typhoid  and  ma- 
larial infection  were  observed  in  soldiers  of  the  U.  S.  Army,  and  are  typical  of 
all  similar  cases  I  have  studied.  In  these  patients  the  malarial  paroxysms 
were  present  during  the  active  symptoms  of  typhoid  fever,  and  although  the 
symptomatology  may  have  been  slightly  altered  by  the  administration  of 
quinine,  the  malarial  infection  was  present  for  a  sufficient  length  of  time  to 
profoundly  alter  the  course  of  the  typhoid,  and  to  give  to  the  temperature  chart 
characteristics  of  a  malarial  infection. 

Coincident  Typhoid  and  Quartan  Malarial  Fevers.— The  following 
case  was  observed  at  the  Sternberg  IT.  S.  Army  General  Hospital,  Chickamauga 
Park,  Ga.,  in  1898,  and  is,  so  far  as  I  know,  the  only  case  recorded  of  coincident 
typhoid  and  quartan  malarial  infection.  The  patient  was  a  Southern  physician 
who  had  suffered  previously  from  repeated  attacks  of  malarial  fever,  but  had 
been  free  from  the  disease  during  the  time  he  was  at  the  Park.  The  clinical 
history  which  follows  is  compiled  from  my  own  observation  and  from  informa- 
tion furnished  me  by  Acting  Assistant  Surgeon  Barnhardt,  U.  S.  Army,  who 
was  in  attendance  upon  the  patient  during  the  latter  portion  of  his  illness  and 
until  his  removal  to  another  hospital. 

Clinical  History. — D.  R.  P.  had  suffered  from  September  29  to  October  5, 
from  general  malaise,  constipation,  and  headache,  with  an  evening  temperature 
of  from  1010  F.  to  1020  F.  Although  feeling  ill  he  did  not  take  to  his  bed  until 
October  5,  when  he  was  admitted  to  the  hospital,  complaining  of  severe  headache 
and  great  nervousness.  The  previous  evening  he  had  had  a  slight  chill.  On 
admission  he  presented  the  following  clinical  symptoms:  Gurgling  and  tender- 
ness in  the  right  iliac  fossa;  a  dry,  hot  skin;  brilliant  eyes,  with  injected  con- 
junctivae; and  a  typical  typhoid  tongue.  The  typhoid  symptoms  gradually 
increased,  and  he  developed  tympanites,  epistaxis,  rose  spots,  extreme  restless- 
ness, and  a  slight  bronchitis. 


288       SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARLAL  FEVERS. 

October  12,  or  about  the  twelfth  day  of  the  fever,  his  blood  was  tested  for 
the  Widal  reaction  and  found  positive,  the  reaction  being  marked;  he  also 
showed  the  diazo-reaction  in  his  urine  The  patient  had  never  had  typhoid 
fever  previously. 

Upon  Obctober  15,  the  morning  temperature  had  fallen  to  ioo°  F.,and 
his  general  condition  appeared  much  improved,  but  later  in  the  day  he  had  a 
slight  chill  and  the  temperature  rose  to  103.4°  F.  The  attending  physician 
thought  little'of  the  chill,  as,  by  evening,  the  temperature  had  fallen  to  ioi°  F., 
and  for  the  succeeding  two  days  ranged  between  ioo°  F.  and  102°  F.  October 
18,  however,  just  72  hours  after  the  first  chill,  a  second  and  more  severe  chill 
occurred,  the  temperature  rising  to  104°  F. 

At  this  time  I  was  called  upon  to  examine  the  blood,  and  found  the  quartan 
malarial  Plasmodium  present  in  large  numbers.  The  blood  examinations  are 
detailed  below.  At  the  time  of  the  first  blood  examination  the  patient's  general 
condition  was  markedly  altered  for  the  worse,  and  he  suffered  from  general 
muscular  pains,  severe  in  character,  a  weak,  irregular  pulse,  and  was  very  weak 
and  tremulous. 

From  October  iS  to  October  21  his  temperature  ranged  between  98. 8° 
to  1 00. 6°  F.  The  administration  of  quinine  in  small  doses  (5  grains  night  and 
morning)  was  begun  upon  October  18.  Upon  October  21,  a  third  paroxysm  oc- 
curred, but  was  delayed  somewhat  (probably  by  the  quinine),  so  that  it  extended 
into  the  2 2d,  the  acme  of  the  fever  being  reached  at  4  a.  m.  of  that  day.  This 
paroxysm  was  very  severe,  the  chill  lasting  thirty  minutes,  and  the  temperature 
rising  from  99. 2°  F.  to  104.6°  F.  A  fourth  paroxysm  occurred  upon  October  25, 
the  quinine,  for  some  reason,  having  been  stopped  upon  the  23d.  A  fifth  paroxysm 
occurred  upon  October  28,  after  which  quinine  in  large  doses  (10  grains  every 
four  hours)  was  given.  Upon  October  31,  a  very  slight  chill  occurred,  with  a 
rise  of  temperature  to  only  102°  F. 

From  this  time  on  the  patient  had  no  further  paroxysms  and  his  tempera- 
ture gradually  reached  normal.  The  convalescence  was  very  slow.  During 
the  malarial  complication  the  patient's  condition  was  that  of  a  desperately  sick 
man,  and  none  of  the  surgeons  who  saw  him  entertained  any  hopes  of  his 
recovery.  He  became  greatly  emaciated  and  very  anaemic,  and  was  delirious 
much  of  the  time.  During  the  entire  time  his  blood  showed  numerous  quartan 
Plasmodia,  corresponding  in  their  development  with  the  time  of  the  paroxysms. 
The  blood  always  gave  a  marked  Widal  reaction  whenever  tested. 

The  following  is  a  brief  summary  of  the  results  of  the  examination  of  the 
blood  in  this  case. 

The  blood  was  first  examined  at  the  time  of  the  second  chill,  when  numerous 
full-grown  and  segmenting  quartan  plasmodia  were  found.  Examinations 
were  made  every  day,  and  plasmodia  were  always  demonstrated  without 
difficulty.  The  last  Plasmodium  observed  in  the  blood  was  a  full-grown  quartan 
organism,  upon  October  31. 

A  record  of  four  days,  which  follows,  shows  the  average  findings  for  that 
period  throughout  the    course  of  the  malarial  fever. 

October  18. — Chill.      Large  numbers  of  full-grown  organisms;  a  few  segment- 


SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARIAL  FEVERS.       289 

ing  plasmodia;  a  few  fragmenting  bodies;  and  a  few  extracellular  and  hyaline 
bodies. 

October  19. — Numerous  hyaline,  unpigmented  plasmodia;  a  few  pigmented; 
and  one  fragmenting  body. 

October  20. — Many  half-grown  and  nearly  three-quarters  grown,  pigmented 
quartan  plasmodia,  a  few  vacuolated. 

October  21. — Many  full-grown  plasmodia;  several  segmenting  bodies;  and 
fragmenting  and  extracellular  bodies. 

A  careful  study  of  the  clinical  chart  (Chart  No.  17.5)  in  this  case  is  of  great 
interest.  Up  to  October  15,  the  twenty-second  day  of  the  typhoid,  the  course  of 
the  fever  had  been  typical,  and  the  temperature  had  begun  to  decline  gradually,  as 
is  characteristic  of  the  disease.  On  the  fifteenth,  following  the  chill,  the  tempera- 
ture rose,  but  instead  of  falling  to  normal  or  below,  which  is  characteristic  of  the 
decline  of  ordinary  malarial  fevers,  it  fell  only  to  the  point  previously  held  by  the 
original  disease.  From  that  time  a  gradual  decline  took  place  in  the  tempera- 
ture until  the  second  chill,  upon  October  18,  when  the  fever  rose  from  99. 40  F. 
to  io4°F.,  but  fell  in  the  course  of  four  hours  to  990  F.  If,  now,  we  discard  the 
rises  in  temperature  due  to  the  malarial  infection,  we  will  observe  that  the 
course  of  the  temperature  is  that  of  a  typical  declining  typhoid,  which  holds 
true  up  to  the  twenty-fourth,  when  the  temperature  between  the  malarial 
jDaroxysms  became  very  irregular.  Prior  to  the  twenty-fourth  the  temperature 
curve  illustrated  most  instructively  how  these  two  diseases,  which  existed 
together,  influenced  the  temperature  chart.  The  malarial  paroxysms  occurred, 
but  did  not  materially  influence  the  course  of  the  typhoid  temperature,  which 
gradually  declined  just  as  it  does  in  uncomplicated  cases,  while  the  temper- 
ature of  the  malarial  paroxysms  was  also  typical  of  that  observed  in  ordinary 
quartan  infections.  This  observation  conclusively  proves  that  a  malarial  in- 
fection may  occur  during  the  active  course  of  typhoid  and  that  each  fever 
preserves  its  characteristic  temperature  curve. 

The  irregularity  of  the  temperature  curve  after  the  twenty-fourth  may  be 
explained  by  the  development  of  severe  hypostatic  congestion,  and  the  extreme 
state  of  nervous  excitability  from  which  the  patient  suffered.  Naturally  of  a 
very  nervous  disposition,  he  was  passing  through  a  very  severe  attack  of  typhoid 
fever,  only  to  be  set  back  and  exhausted  by  the  severe  chills  and  high  fever 
which  accompanied  the  malarial  infection;  he  became  extremely  nervous  and 
discouraged,  and  so  changed  in  appearance  that  one  would  recognize  at  a  glance 
the  terrific,  strain  under  which  he  was  struggling.  He  came  to  look  forward 
with  the  utmost  dread  to  the  chills;  and  this  intensely  nervous  condition,  taken 
with  the  hypostatic  congestion,  undoubtedly  explains  the  irregularity  of  the 
temperature  toward  the  latter  part  of  his  disease.  It  may  be  possible  that 
there  was  a  multiple  infection  with  the  quartan  plasmodia,  but  the  blood  findings 
would  appear  to  preclude  this. 

It  will  be  observed  that  the  fever  was  very  resistant  to  small  doses  of 
quinine,  but  that  large  doses  of  this  drug  reduced  it  very  promptly.     The 
19 


290       SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARIAL  FEVERS. 


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292       SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARLA.L  FEVERS. 

patient  was  convalescent  when  I  lost  sight  of  him,  but  I  have  since  learned  that 
he  died  of  pneumonia  several  weeks  later.  This  case  is  of  especial  interest 
because  the  type  of  malaria  present  was  the  quartan  variety,  a  form  very  rare 
even  in  malarial  localities  in  the  United  States. 

The  two  following  cases  of  combined  typhoid  and  aestivo-autumnal  ma- 
larial fever  are  fairly  typical  of  such  infections  and  occurred  in  soldiers  of  the 
U.  S.  Army. 

Case  I. — S.  J.  Colored.  Was  admitted  to  the  hospital  suffering  from 
typhoid  fever  and  presenting  the  usual  signs  and  symptoms  of  that  disease. 
Date  of  admission,  March  16,  1899.  Had  been  sick  for  two  weeks  before  ad- 
mission, but  had  had  no  chills.  Upon  the  seventeenth  of  March  he  had  a  chill 
and  his  temperature  rose  to  104. 40  F.  He  suffered  from  headache,  backache, 
and  nausea.  Physical  examination  showed  an  enlarged  spleen ;  tender  abdomen ; 
hot,  dry  skin;  and  suffused  and  brilliant  eyes.  An  examination  was  made  of 
his  blood  and  numerous  "ring-forms"  of  the  tertian  aestivo-autumnal  Plasmo- 
dium were  found,  every  microscopic  field  showing  one  or  more.  Quinine  was 
at  once  administered,  but  as  the  temperature  did  not  decline  the  Widal  test  was 
made  and  a  marked  reaction  was  obtained.  All  of  the  typical  symptoms  of 
typhoid  fever  was  present,  and  the  course  of  the  disease,  after  the  malarial 
complication  was  eliminated  by  quinine,  was  that  of  a  gradually  declining 
typhoid. 

In  this  case  it  will  be  observed  that  the  malarial  complication  occurred 
during  the  acute  stage  of  the  typhoid,  and  a  study  of  the  chart  (Chart  No.  18) 
will  demonstrate  how  little  the  malaria  affected  the  course  of  the  typhoid,  and 
that  but  for  the  microscope  the  diagnosis  of  the  malarial  infection  could  hardly 
have  been  made. 

Case  II. — This  case,  observed  at  the  U.  S.  Army  General  Hospital, 
Presidio  of  San  Francisco,  Cal.,  occurred  in  the  practice  of  Captain  Bevans, 
Medical  Corps,  and  I  am  indebted  to  him  for  the  clinical  notes  upon  the  case, 
which  are  given  in  his  own  words. 

"Corporal  R.  M.  Co.  K,  29th  U.  S.  V.  Inft.  Aged  21,  born  in  Tennessee, 
was  admitted  on  October  3,  1899.  The  man  lived  in  his  native  State  until 
enlistment  in  the  Fourth  Tennessee  Volunteer  Infantry  in  the  fall  of  1898. 
He  then  served  in  Cuba,  and  during  his  first  service  had  a  few  light  chills,, 
which  continued  after  his  return  home  and  until  his  reenlistment  in  August 
1899.  The  chills  appeared  again  at  Fort  McPherson,  where  he  stayed  about  a 
month,  and  continued  irregularly  up  to  the  time  of  his  present  sickness.  En- 
route  to  the  Presidio,  where  he  arrived  October  1,  he  was  confined  to  his  bed 
with  headache,  light  chills,  and  general  malaise.  He  had  not,  previous  to  that 
time,  been  on  sick  report.  After  three  days  in  quarters  in  camp  he  was  sent  to 
the  General  Hospital.  As  he  was  brought  into  the  ward  he  appeared  pale, 
emaciated,  and  cold.  His  temperature  was  102. 40  F.,  respiration  22,  and  pulse 
94.  His  tongue  was  coated,  the  abdomen  tender,  the  liver  and  spleen  some- 
what enlarged.     His  mental  condition  was  dazed.     By  October  7  rose  spots  had 


SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARIAL  FEVERS.       293 

developed  and  he  was  in  an  active  delirium.  He  had  involuntary  passages  of 
urine  and  faeces.  Light  chills  occurred  daily  after  the  sixth.  On  the  eleventh 
the  chill  was  prolonged  and  severe.  Malarial  parasites  were  first  found  in  the 
blood  upon  that  day.  Quinine  was  then  administered  in  large  doses  and  the 
last  chill  was  observed  two  days  later.  Delirium  continued  until  the  twenty- 
fifth.  The  temperature  curve  and  symptoms  after  the  thirteenth  were  those  of 
typhoid  fever.  The  temperature  reached  normal  on  the  twenty-ninth,  and 
slow  convalescence  has  taken  place." 

Captain  Bevans  asked  me  to  examine  the  blood  in  this  case  upon  the 
fourth  of  October,  and  also  to  make  a  Widal  test,  but  both  examinations  were 
negative,  and  it  was  not  until  the  eleventh  that  I  was  able  to  demonstrate  the 
Plasmodia  in  the  blood  and  the  Widal  test  was  not  positive  until  after  the  tem- 
perature had  become  normal.  The  late  appearance  of  the  positive  reaction  to 
the  Widal  test  is  of  interest,  as  in  other  cases  of  coincident  typhoid  and  malarial 
infection  the  response  to  the  Widal  test  has  always  been  prompt.  Upon  the 
eleventh  of  October  numerous  "ring-forms"  of  the  tertian  aestivo-autumnal 
Plasmodium  were  found  in  the  blood,  which  soon  disappeared  after  the  ad- 
ministration of  quinine.  The  chart  in  this  case  is  not  given  as  it  is  not  typical 
of  anything  but  an  ordinary  typhoid  with  a  sudden  rise  of  temperature  marking 
the  occurrence  of  the  malarial  paroxysm. 

From  the  examples  of  coincident  typhoid  and  malarial  fever  which  have 
been  given  it  is  evident  that  Woodward's  definition  of  typho-malarial  fever  as  a 
hybrid  disease  presenting  certain  characteristic  symptoms  is  not  borne  out,  for 
there  was  nothing  in  any  of  these  cases  which  would  differentiate  them  from 
ordinary  typhoid  with  the  exception  of  the  occurrence  of  chills,  but  chills  also 
occur  in  typhoid  uncomplicated  with  malaria,  and  where  septic  infection 
exists.  I  think  it  may  be  stated  with  truth  that  no  one  of  the  symptoms  de- 
scribed by  Woodward  as  characteristic  of  typho-malarial  fever  has  been  proven 
by  recent  research  to  be  so,  and  Dock,  in  an  excellent  discussion  of  this  sub- 
ject, in  which  he  gives  the  conclusions  of  years  of  study,  states  that  "we  find 
that  the  belief  in  a  characteristic  disease  composed  of  typhoid  and  malarial 
elements  is  not  based  on  sufficient  evidence,"  and  with  this  statement  I  am  fully 
in  accord. 

The  prognosis  in  cases  of  coincident  typhoid  and  malarial  infection  is 
always  grave  and  it  is  the  concensus  of  opinion  of  all  who  have  observed  such 
cases  that  during  the  malarial  paroxysms  the  patient  appears  to  lose  ground 
rapidly,  and  that  the  occurrence  of  malarial  infection  during  an  attack  of 
typhoid  appears  to  increase  the  severity  of  the  symptoms  of  that  disease. 

The  recognition  of  these  cases  is  of  great  importance,  especially  in  regions 
in  which  the  aestivo-autumnal  fevers  are  prevalent,  but  it  should  be  remem- 
bered that  such  recognition  is  only  possible  by  the  use  of  the  microscope,  and 
quinine  should  never  be  administered  to  a  patient  suffering  from  typhoid  fever, 
presenting  atypical  symptoms,  unless  the  malarial  plasmodia  can  be  demon- 
strated in  the  blood,  for  while  the  administration  of  this  drug  is  always  beneficial 


294       SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARIAL  FEVERS. 


SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARIAL  FEVERS.       295 


296       SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARIAL  FEVERS. 

in  malaria,  it  is  always  harmful  in  typhoid.  Thayer  has  very  aptly  discussed 
this  point  as  follows: 

"The  mere  use  of  the  term  typho-malarial  fever  has  indicated  to  many  the 
advisability  of  the  administration  of  quinine,  and  not  infrequently  this  drug  is 
used  for  days  and  for  weeks  in  cases  of  uncomplicated  typhoid  fever  in  doses 
which  cannot  but  be  injurious  to  the  patient.  This  is  a  matter  of  really  grave 
importance.  It  is  one  of  the  positions  in  which  the  physician  actually  has  done 
and  does  do,  to-day,  really  serious  harm  to  his  patient.  There  is  no  excuse  for 
cinchonizing  an  individual  with  continuous  fever  who,  after  three  or  four  days, 
shows  no  change  in  the  symptoms,  while  the  blood  is  free  from  malarial 
parasites." 

This  statement  of  Thayer's  has  been  borne  out  in  my  own  experience  for  I 
have  more  than  once  observed  cases  in  which  the  attending  physician  had  ad- 
ministered quinine  in  doses  of  from  40  to  60  grains,  for  four  weeks,  in  typical 
attacks  of  typhoid  fever,  under  the  impression  that  the  disease  was  really  typho- 
malarial  fever  or  remittent  malaria.  Such  treatment  is  nothing  less  than 
criminal  and  cannot  be  too  strongly  condemned.  The  use  of  the  term  "typho- 
malaria"  should  be  entirely  discarded  in  medical  nomenclature,  for  its  retention 
will  lead  inevitably  to  the  extensive  use  of  quinine  in  atypical  cases  of  typhoid 
fever. 

Osier's  dictum,  that  any  continued  fever  which  resists  the  use  of  quinine 
for  over  five  days  is  not  malarial  in  character,  has  been  proven  by  every  experi- 
enced practitioner  in  malarial  localities  to  be  true,  and  I  am  convinced  that  the 
vast  majority  of  malarial  fevers  are  checked  or  markedly  affected  by  this  drug 
within  three  days  of  its  administration,  and  that  it  is  folly  to  continue  giving 
quinine  in  fevers  which  resist  its  action  for  more  than  five  days. 

While  it  is  the  testimony  of  all  practitioners  who  have  had  much  to  do  with 
the  malarial  fevers  that  the  above  statement  is  true,  it  is  still  all  too  common  to 
observe  the  indiscriminate  and  continued  use  of  this  drug  in  typhoid  fever,  often 
to  the  great  injury  of  the  patient.  A  microscopical  examination  of  the  blood 
would  obviate  this  mistake,  and  quinine  should  never  be  administered  in 
typhoid  fever  unless  such  an  examination  demonstrates  the  presence  of  malarial 
Plasmodia. 

Literature  upon  Coincident  Typhoid  and  Malarial  Infection. 

1863.  Woodward.  Outline  of  the  Chief  Camp  Diseases  of  the  United  States 
Armies,  as  Observed  During  the  Present  War.     Philadelphia. 

1864.  Levick.  Miasmatic  Typhoid  Fever.  The  American  Jour.  Med.  Sciences, 
April. 

1867.  Bartholow.  Camp  Fevers.  Memoirs  of  the  United  States  Sanitary 
Commission,  New  York. 

1870.  The  Medical  and  Surgical  History  of  the  War  of  the  Rebellion.  Wash- 
ington.     Part  r,  vol.  i. 

1875.  Cochran.  Typho-malarial  Fever.  Trans.  Med.  Assoc.  State  of  Alabama, 
28th  session,  Note  B.  I. 


SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARIAL  FEVERS.       297 

876.      Woodward.      Typho-malarial    Fever:      Is   it   a    Special   Type  of   Fever? 

Trans.  International  Med.  Congress,   Philadelphia. 
888.      Cahn.      De  la  marche  de  la  fievre  typhoid  chez  les  paludeens.      Thesis 

de  Paris. 
890.      Kinyoun.      Enteromalarial     Fever.      Abstract     of     Sanitary     Reports 

Marine  Hospital  Bureau,  vol.  v. 
892.     Gancel.      Etude  sur  la  fievre  typho-palustre.     Arch.  Med.  et  Pharmacy, 

Milit,  Paris. 
892.      Young.      Typho-malarial  Fever,    so-called.      Med.   and   Surg.    Reporter, 

vol.  lxvii. 

894.  Thompson.  Notes  on  the  Observations  of  Malarial  Organisms  in  Con- 
nection with  Enteric  Fever.      Trans.  Assoc.  Amer.  Phys.,  vol.  ix. 

895.  Osler.  Chills  in  Typhoid  Fever.  University  Med.  Magazine,  Novem- 
ber. 

89  5.  Vincent.  Sur  la  symptomatology  et  la  nature  de  la  fievre  typhopalustre. 
Le  Mercredi  Medical,  December  4,  vol.  vi. 

897.  Da  Costa.  The  Coexistence  of  Typhoid  and  Malarial  Infection.  Inter- 
national Clinics,  Seventh  Series,  vol.  ii. 

897.  Osler.      The  Diagnosis  of  Malarial  Fever.      The  Med.  News,  March  6. 

898.  Cardamantis  and  Canellis.  Etude  clinique  sur  le  typhisme,  sur  la 
fievre  continue  paludeenne  et  sur  la  fievre  typho-malarienne.  Le 
Progres  Medicale,  March  26,  April  23  and  30. 

899.  Lyon.  Combined  Typhoid  and  Malarial  Infection.  Amer.  Jour.  Med. 
Sciences,  January. 

Dock.     Typho-malarial  Fever,  So-called.      N.  Y.  Medical  Jour.,  Feb.  25. 
Ewing.      Preliminary  Report  on  the  Results  of  Blood  Examinations  at 
Camp  Wikoff,  etc.,  N.  Y.  Med.  Jour.,  Jan.  28  and  Feb.  4. 
Craig,  C.    F.      Report    of   a   Case   of   Combined   Typhoid   and    Quartan 
Malarial  Fevers.     Philadelphia  Med.  Jour.,  June  17. 
Muehleck.      Philadelphia  Med.  Jour.,  May  20,  1899,  p.  11 16. 

1900.      Bevans.      A  Case  of  Mixed  Typhoid  and  Malarial  Fevers.      N.  Y.  Med. 

Jour.  Feb.  10. 
1902.      Rho.      Annals  Med.  Navale,  1902. 
1904.     Reed,    Vaughn   and    Shakespeare.      Rep.    on   Origin    and    Spread   of 

Typhoid  Fever,  etc.      U.  S.  Gov't  Printing  Office,  p.  645 


CHAPTER  IV. 

The  Prognosis  of  the  Malarial  Fevers. 

If  one  were  to  draw  his  deductions  concerning  the  prognosis  of  the  malarial 
fevers  from  the  vital  statistics  of  the  cities  and  towns  of  the  United  States,  he 
could  not  but  conclude  that  the  prognosis  in  these  fevers  is  very  bad,  for  the 
number  of  deaths  ascribed  to  malaria  in  such  statistics  is  very  great.  In  speak- 
ing of  this  Osier  calls  attention  to  the  fact  that  while  in  temperate  climates  it 
is  well  known  that  the  prognosis  in  malaria  is  most  favorable,  still  the  vital 
statistics  in  some  of  our  large  cities  show  a  greater  death  rate  for  malaria  than 
for  typhoid  fever.     He  says: 

"In  the  United  States  Census  Report  of  1890,  which  covers  the  six  preceding 
years,  the  deaths  from  malarial  fever  in  New  York  and  Brooklyn  were  more 
numerous  than  from  typhoid  fever.  In  both  these  cities  it  is  notorious  that  a 
death  from  malarial  fever  is  a  great  rarity.  No  more  than  three  or  four  cases 
occur  each  year  in  the  entire  hospital  practice  of  the  city  of  New  York." 

Nothing  could  illustrate  more  forcibly  the  immense  importance  of  a 
scientific  diagnosis  of  malarial  fevers  by  an  examination  of  the  blood  than  does 
this  quotation,  and  the  condition  of  ignorance  of  the  true  nature  of  malaria 
which  it  portrays  is  a  reproach  to  American  medicine. 

General  Factors  Influencing  Prognosis. — Certain  general  factors 
should  be  taken  into  consideration  in  estimating  the  prognosis  of  the  malarial 
fevers,  the  chief  of  which  are  locality,  race,  age,  occupation,  and  physical  and 
social  condition  of  the  patient. 

Locality. — In  certain  localities  the  prognosis  of  malaria  is  much  more 
grave  than  it  is  in  others.  In  the  tropics  the  prognosis  of  all  varieties  of  ma- 
larial fever  is  more  grave  than  it  is  in  temperate  regions,  this  being  true  of  the 
aestivo-autumnal  infections  as  well  as  of  the  quartan  and  tertian  infections. 
Again,  in  certain  regions  in  the  tropics  the  aestivo-autumnal  fevers  are  much 
more  fatal  than  in  others.  For  instance,  these  fevers  are  more  fatal  in  Santiago, 
Cuba,  than  they  are  in  Havana,  although  the  climate  is  practically  the  same. 
The  prognosis  of  malaria  in  the  tropics  should  always  be  guarded,  for  here  we 
meet  with  most  of  the  pernicious  types  of  fever,  and  the  aestivo-autumnal 
infections  occur  in  most  cases,  and  in  them  the  prognosis  is  always  grave. 

Race. — The  negro  and  many  native  races  in  the  tropics  enjoy  a  relative 
immunity  to  the  effects  of  the  malarial  plasmodia,  acquired  through  repeated 
attacks  during  childhood  and  early  youth;  but  in  regions  in  which  only  the 
aestivo-autumnal  fevers  are  present,  while  an  immunity  may  be  present  against 
them,  exposure  in  another  locality  to  tertian  or  quartan  infection  may  result  in 

298 


SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARIAL  FEVERS.       299 

severe  attacks  of  these  forms  and  the  prognosis  in  individual  cases  may  be  grave. 
As  a  general  rule,  it  may  be  stated  that  in  adult  natives,  living  in  infected  regions, 
the  prognosis  of  malaria  is  good,  even  severe  infections  being  rapidly  recovered 
from. 

Age. — The  prognosis  is  most  grave  at  the  extremes  of  life.  In  very  young 
infants  and  in  the  aged  the  prognosis  of  the  aestivo-autumnal  fevers  is  always 
very  grave. 

Occupation. — Certain  occupations,  by  decreasing  the  resisting  powers  of 
the  individual,  render  the  prognosis  of  malaria  very  grave,  especially  if  the 
aestivo-autumnal  infections  be  present.  All  occupations  leading  to  anaemia, 
loss  of  muscular  strength,  and  deficient  nutrition,  increase  the  gravity  of  the 
prognosis  in  the  malarial  fevers. 

Physical  and  Social  Condition  of  the  Patient. — It  is  obvious  that  the 
prognosis  in  patients  suffering  from  organic  disease  or  severe  functional  disorders 
will  be  more  grave  than  in  the  case  of  those  who  have  previously  been  in  good 
health,  and  in  individuals  weakened  by  long-continued  disease  or  by  severe 
attacks  of  other  acute  fevers  the  prognosis,  especially  in  aestivo-autumnal 
infections,  is  always  grave. 

The  social  condition  of  the  patient  has  much  to  do  with  the  severity  of 
a  malarial  attack  and  markedly  influences  prognosis.  The  prognosis  in  the 
well-to-do  is  always  more  favorable  than  in  the  poor,  both  because  the  physical 
condition  of  the  first  class  is  better,  as  a  rule,  than  that  of  the  second,  and  because 
in  the  first  class  the  disease  is  at  once  treated,  while  in  the  second,  because  of 
the  fear  of  expense,  a  physician  is  not  called,  and  repeated  attacks  may  occur 
before  treatment  is  instituted.  The  prognosis  in  the  case  of  laborers  who  have 
been  exposed  to  repeated  malarial  infection  and  in  soldiers  serving  in  tropical 
climates  is  always  grave,  as  has  been  conclusively  proven  in  the  case  of  laborers 
upon  the  Panama  Canal  and  in  our  soldiers  in  Cuba  and  the  Philippine  Islands. 
While  intelligent  treatment  has,  in  the  vast  majority  of  cases,  prevented  a  fatal 
termination  of  the  acute  attack,  the  debility  and  anaemia  occasioned  by  repeated 
recurrences  have  often  induced  a  state  of  chronic  invalidism,  and  in  many  cases 
death  has  eventually  resulted.  In  considering  in  detail  the  prognosis  in  the 
malarial  fevers,  I  shall  discuss  the  prognosis  in  each  variety  of  infection  sepa- 
rately, as  by  doing  so  we  can  arrive  at  a  more  just  conception  of  the  prognosis 
as  it  is  affected  by  the  occurrence  of  certain  symptoms. 

Tertian  and  Quartan  Infections. — The  prognosis  in  cases  of  uncompli- 
cated tertian  and  quartan  malarial  infection  is  good,  but  it  should  be  remembered 
that  fatal  cases  of  both  these  forms  of  malaria  have  been  reported,  and  in 
tropical  regions  the  prognosis  in  the  quartan  infections,  especially,  should  be 
guarded,  as  very  often  these  infections  are  resistant  to  treatment,  recur  fre- 
quently, and  may  assume  pernicious  forms  at  any  time. 

Quotidian  Aestivo-autumnal  Malaria. — The  prognosis  in  cases  of 
quotidian  aestivo-autumnal  fever,  provided  they  are  not  pernicious  in 
character  and  treatment  is  begun  promptly,  is  always  favorable  so  far  as  im- 


300       SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARL4.L  FEVERS. 

mediate  danger  to  life  is  concerned.  If,  however,  treatment  is  not  persisted  in 
for  several  weeks  after  the  symptoms  have  disappeared,  relapses  almost  invari- 
ably occur,  producing  marked  anaemia  and  debility,  and  in  such  cases  the  prog- 
nosis should  be  more  guarded.  Several  times  I  have  observed  fatal  cases  of 
anaemia  following  attacks  of  this  form  of  malarial  fever,  in  one  case  the  red 
blood-corpuscles  falling  to  400,000  per  cubic  millimeter  before  death. 

In  cases  which  are  unrecognized  or  improperly  treated  the  prognosis  is 
grave.  Repeated  relapses,  together  with  the  complications  which  may  arise, 
render  a  favorable  prognosis  as  to  ultimate  cure  impossible.  When  complica- 
tions, such  as  pneumonia,  nephritis,  dysentery,  and  severe  nervous  conditions, 
accompany  the  paroxysms  the  prognosis  is  grave  and  should  be  very  guarded. 

In  all  infections  with  the  quotidian  aestivo-autumnal  plasmodium  the  prog- 
nosis given  should  be  influenced  by  the  fact  that  pernicious  symptoms  are  apt 
to  develop  at  any  time. 

Tertian  Aestivo-autumnal  Malaria. — In  uncomplicated  cases  of  tertian 
aestivo-autumnal  fever,  properly  treated,  the  prognosis  is  good.  If,  however, 
the  patient  has  suffered  from  previous  attacks  and  is  greatly  debilitated  by 
them  the  prognosis  is  much  more  grave,  as  such  infections  are  often  very 
resistant  to  treatment.  This  heightened  resistance  is  probably  due  to  dimin- 
ished ability  to  absorb  quinine  or  to  a  more  resistant  form  of  the  plasmodium. 
In  cases  in  which  grave  complications,  such  as  nephritis  and  cardiac  disease 
are  present,  the  prognosis  should  be  guarded,  and  often  depends  quite  largely 
upon  the  nature  and  severity  of  the  complication.  In  untreated  cases  of 
tertian  aestivo-autumnal  malaria  the  prognosis  is  grave,  and  the  liability  of  this 
form  of  infection  to  develop  pernicious  symptoms  should  always  be  considered 
in  giving  a  prognosis.  While  formerly  I  considered  that  the  prognosis  in 
tertian  aestivo-autumnal  fever  was  more  favorable  than  in  the  quotidian  form, 
further  observation  has  led  me  to  believe  that  very  little  difference  exists 
between  the  two  forms  as  regards  prognosis.  While  a  greater  number  of 
pernicious  cases,  in  which  the  result  has  been  fatal,  have  been  found  to  be 
infected  with  the  tertian  aestivo-autumnal  plasmodium,  I  cannot  help  but 
believe  that  this  is  largely  due  to  the  more  frequent  occurrence  of  the  tertian 
infections,  and  that  further  investigation  will  demonstrate  that  the  quotidian 
plasmodium  produces  as  severe  infections  as  does  the  tertian  species. 

The  Pernicious  Forms  of  Malarial  Fever. — As  I  have  already  stated, 
pernicious  forms  of  malaria  may  be  produced  by  any  of  the  species  of  malarial 
Plasmodia,  although  the  vast  majority  of  such  forms  are  due  to  the  aestivo- 
autumnal  plasmodia.  Whatever  the  species  concerned  in  their  etiology,  the 
prognosis  is  practically  the  same,  and  depends  more  upon  the  character  of  the 
symptoms  produced  than  upon  the  species  of  plasmodium  present. 

The  prognosis  in  the  pernicious  cases  varies  with  the  number  of  paroxysms 
which  have  occurred  and  the  clinical  character  of  the  attack.  If  the  patient 
is  first  seen  after  having  suffered  from  one  or  more  pernicious  paroxysms,  the 
prognosis  is  very  grave  although,  if  treatment  be   rigorously   instituted,  not 


SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARIAL  FEVERS.       3OI 

hopeless.  If  seen  during  the  first  paroxysm,  the  prognosis  is  grave,  and 
treatment  should  be  at  once  instituted.  In  such  cases  a  fatal  paroxysm  may 
follow,  even  after  the  most  energetic  treatment. 

The  Cerebral  Pernicious  Forms. — The  prognosis  is  very  grave  in  those 
forms  of  pernicious  malaria  which  exhibit  cerebral  symptoms.  This  is  espe- 
cially true  of  the  comatose  form  in  which  the  prognosis  is  always  most  grave.  A 
large  number  of  such  cases  recover  with  proper  treatment,  but  this  form  furnishes 
the  greater  number  of  cases  of  fatal  pernicious  malarial  fever.  The  forms 
characterized  by  delirium  and  acute  maniacal  attacks  also  are  of  grave  prognosis. 
Untreated,  the  cerebral  forms  of  pernicious  malaria  are  almost  invariably  fatal. 

The  Algid  Form. — The  prognosis  in  the  algid  form  is  almost  as  grave  as  it 
is  in  the  cerebral  forms,  and  such  cases,  if  untreated,  are  usually  fatal.  Prompt 
treatment  will  save  many,  but  not  a  few  terminate  fatally  despite  all  treat- 
ment. The  prognosis  as  to  ultimate  recovery  in  the  algid  form  is  unfavorable, 
as  convalescence  is  slow,  the  patient  greatly  weakened,  and  relapses  are  apt  to 
occur. 

The  Choleraic  Form. — The  prognosis  in  this  form  is  very  grave  and 
Marchiafava  and  Bignami  believe  that  this  form  ranks  next  to  the  cerebral 
forms  in  fatality. 

The  Dysenteric  Form. — The  prognosis  in  the  dysenteric  form  of  aestivo- 
autumnal  fever  is  grave,  and  I  have  observed  several  cases  which  resulted 
fatally  despite  all  treatment,  but  only  where  treatment  was  delayed  for  several 
days  after  the  onset  of  the  symptoms.  The  prognosis  in  these  cases  should  de- 
pend largely  upon  the  severity  of  the  dysenteric  symptoms  and  the  degree  of 
anaemia  present.  The  paroxysms  are  apt  to  be  hidden  by  the  intestinal 
phenomena,  and  the  malarial  element  thus  remains  long  undetected  before 
treatment  is  instituted.  Death  is  usually  the  result  of  exhaustion  and  anemia 
in  these  cases.  If  treatment  be  promptly  instituted  most  cases  of  dysenteric 
pernicious  fever  will  recover,  but  an  irritable  condition  of  the  bowels  persists 
for   some  time  afterward. 

The  Pneumonic  Form. — In  the  pneumonic  form  the  prognosis  is  always 
grave  and,  if  untreated,  a  large  proportion  of  such  cases  terminate  fatally. 
This  form  is  so  rare  that  it  is  difficult  to  estimate  the  relative  gravity  of  it  and 
the  other  forms  of  pernicious  malaria,  but  I  believe  that  untreated  it  is  a  very 
fatal  form  of  malaria. 

Other  Pernicious  Forms. — The  prognosis  in  the  other  pernicious  forms 
of  malarial  fever,  as  the  diaphoretic,  cardialgic,  haemorrhagic,  and  the  forms 
characterized  by  convulsions  and  paralysis,  is  always  grave,  and  these  cases 
demand  immediate  treatment. 

Prognosis  in  Irregular  and  Sub-continued  Fevers. — The  prognosis  in 
the  irregular  and  sub-continued  malarial  fevers  differs,  of  course,  with  the 
severity  of  the  symptoms  present,  but  it  is  always  more  grave  than  in  the 
regularly  intermittent  fevers,  but  less  so  than  in  the  pernicious  forms.  As  these 
infections  are  very  apt  to  be  considered  of  non-malarial  nature,  they  may  have 


3<D2       SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARIAL  FEVERS. 

persisted  for  some  time  before  treatment  is  instituted,  and  this,  of  course,  renders 
the  prognosis  more  grave  than  it  would  otherwise  be.  Most  of  these  cases, 
however,  recover  promptly  under  the  proper  administration  of  quinine. 

Prognosis  in  Complicated  Cases  of  Malaria. — The  prognosis  in  cases  of 
malarial  fever  attended  by  important  complications  is  that  of  the  type  of 
malaria  present  and  the  added  complication.  It  is  always  more  grave  than  in 
uncomplicated  cases.  Among  the  complications  which  render  the  prognosis 
very  grave  may  be  mentioned  pneumonia,  the  infectious  fevers,  tuberculosis, 
sunstroke,  and  typhoid  fever. 

Prognosis  of  the  Sequelae  of  Malaria. — As  a  general  rule,  it  may  be 
stated  that  the  prognosis  of  the  sequelae  of  the  malarial  fevers  is  good,  recovery 
usually  occurring  within  a  few  weeks  or  months.  The  most  important  of  the 
sequelae  will  be  considered  in  detail. 

Nervous  and  Mental  Sequelae. — The  prognosis  in  the  various  nervous 
and  mental  sequelae  is  good  and  recovery  usually  occurs  within  a  few  weeks,  even 
in  cases  in  which  paralysis  has  followed  a  malarial  attack.  Insanity,  occurring 
as  a  sequela  of  malaria,  does  not  generally  persist  for  more  than  six  months, 
although  there  may  be  impairment  of  the  mental  faculties  for  a  long  time  after- 
ward. The  condition  of  melancholia,  so  often  observed  following  severe 
malarial  attacks,  especially  in  our  soldiers  serving  in  the  Philippines,  is  quickly 
recovered  from  under  the  persistent  use  of  quinine,  and  upon  a  change  of 
station  to  the  United  States. 

Nephritis. — The  majority  of  cases  of  nephritis  occurring  with,  or  following 
the  malarial  fevers  are  rapidly  recovered  from  and  the  prognosis  is  good.  A 
few  cases  become  subacute  or  chronic,  and  in  rare  instances  the  acute  nephritis 
occurring  as  a  complication  terminates  fatally. 

Postmalarial  Anaemia. — The  various  types  of  anaemia  occurring  as 
sequelae  of  the  malarial  fevers  have  already  been  described,  and  it  may  be  said 
that  the  prognosis  depends  entirely  upon  the  character  of  the  anaemia.  In 
simple  anaemia  following  malaria  the  prognosis  is  generally  good,  the  blood 
regaining  the  normal  number  of  red  corpuscles  after  a  period  of  days,  weeks,  or, 
in  the  more  severe  secondary  forms,  months.  This  recovery  often  occurs  in 
cases  in  which  the  red  corpuscles  have  been  very  seriously  reduced  in  number, 
and  I  have  observed  cases  in  which,  after  repeated  attacks  of  aestivo-autumnal 
fever,  the  red  blood  count  was  less  than  1,000,000  per  cubic  millimeter,  but  in 
which  a  return  to  normal  was  observed  within  a  month.  As  a  rule,  in  the  more 
severe  cases  of  secondary  anaemia  the  red  cells  increase  in  number  rapidly  until 
they  reach  2,000,000  per  cubic  millimeter,  after  which  the  increase  is  very  slow, 
and  it  may  be  months  before  the  normal  number  of  red  cells  is  attained. 

The  prognosis  in  those  cases  in  which  the  anaemia  following  malaria 
assumes  the  pernicious  type  is  always  most  grave,  death  usually  resulting  within 
a  few  months. 

Malarial  Cachexia. — In  cases  of  malarial  cachexia  in  which  a  change  of 
climate  is  possible,  the  prognosis,  under  suitable  treatment  is  excellent,  but  in 


SEQUELAE,  COMPLICATIONS,  AND  PROGNOSIS  OF  MALARIAL  FEVERS.       303 

those  cases  which  are  unable  to  leave  the  locality  in  which  they  have  contracted 
their  infection  the  prognosis  is  always  grave  as  to  ultimate  recovery,  and  such 
patients  usually  succumb  to  some  intercurrent  disease  to  which  they  are  ren- 
dered less  resistant  because  of  the  weakened  condition  brought  about  by  the 
long-continued  malarial  poisoning. 

In  estimating  the  prognosis  in  the  malarial  fevers  it  is  usually  possible,  in 
all  but  the  pernicious  forms,  to  give  a  favorable  prognosis  as  to  immediate 
recovery  from  the  malarial  attack,  but  the  physician  should  always  give  a 
guarded  prognosis  as  to  ultimate  cure,  unless  he  can  be  satisfied  that  the 
patient  will  pursue  faithfully  an  extended  treatment  with  quinine.  Relapses 
are  sure  to  occur,  especially  in  the  aestivo-autumnal  infections,  unless  quinine 
is  given  for  weeks  after  the  first  paroxysm,  and  very  often  a  change  of  climate 
is  found  necessary  before  the  infection  can  be  overcome.  One  of  the  most 
discouraging  features  of  the  aestivo-autumnal  fevers  is  the  extreme  tenacity  of 
these  infections,  and  it  is  a  great  mistake  for  the  physician  to  assure  the  patient 
that  he  is  cured  because  the  administration  of  quinine  has  resulted  in  the  cessa- 
tion of  the  symptoms  of  an  acute  attack.  The  physician  who  does  not  insist 
upon  his  malarial  patients  persisting  in  the  use  of  quinine  for  weeks  after 
the  disappearance  of  the  acute  symptoms  fails  in  his  duty  to  the  patient  and  to 
himself. 

In  the  prognosis  of  the  malarial  fevers  the  following  axiom  should  never 
be  forgotten:  The  prognosis  in  all  cases  of  aestivo-autumnal  malaria  is 
grave,  because  pernicious  symptoms  may  arise  at  any  time  during  their  course. 


PART  V. 

THE  DIAGNOSIS,  PROPHYLAXIS,  AND    TREATMENT  OF  THE 
MALARIAL  FEVERS. 


CHAPTER  I. 

The  Laboratory  Diagnosis  of  the  Malarial  Fevers;  Staining  Methods;  Exami- 
nation of  the  Blood;     Examination  of  Malarial  Mosquitoes. 

The  diagnosis  of  the  malarial  fevers  may  be  considered  from  two  stand- 
points: the  diagnosis  by  laboratory  methods  and  the  diagnosis  from  the  clinical 
character  of  the  fevers.  As  I  have  tried  to  make  plain,  it  is  only  in  the  most 
typical  cases  of  malarial  fever  that  we  are  able  to  arrive  at  a  diagnosis  from  the 
clinical  symptoms  alone,  and  therefore  that  the  diagnosis  of  malaria,  and 
especially  of  the  type  of  malaria,  should  always  rest  upon  the  results  of  a  blood 
examination. 

The  importance  of  the  use  of  laboratory  methods  in  the  diagnosis  of  the 
malarial  fevers  cannot  be  too  strongly  emphasized,  and  when  we  remember 
that  the  technic  is  not  difficult,  requires  but  a  few  moments  of  time,  and  but  a 
very  small  amount  of  laboratory  apparatus,  it  is  evident  that  there  is  no  excuse 
for  the  neglect  of  this  method  of  diagnosis.  The  plea,  so  often  urged  by  the 
busy  practitioner,  that  he  has  not  the  time,  can  be  seldom  urged  truthfully,  and 
when  true  is  no  excuse,  as  it  is  possible,  in  most  regions,  to  secure  the  services  of 
some  one  who  is  familiar  with  methods  of  blood  examination  and  who  has  the 
time  to  devote  a  few  moments  to  the  study  of  the  blood  of  a  suspected  case.  I 
have  seen  so  much  misery  result  from  the  neglect  of  blood  examinations  in  fever 
cases,  even  the  death  of  the  patient  in  some  instances,  that  I  feel  that  I  cannot 
urge  too  strongly  the  vital  importance  of  such  examinations  in  all  cases  of  fever. 
I  believe  that  the  time  will  come  when  it  will  be  considered  malpractice  to 
neglect  the  blood  examination  in  fever  cases,  and  that  he  who  loses  a  patient 
from  malaria  and  has  not  recognized  the  disease  because  of  the  neglect  of  a 
blood  examination  will  be  amenable  to  the  law. 

The  examination  of  the  blood  is  the  quickest  and  most  reliable  method  of 
diagnosing  any  of  the  varieties  of  malarial  fever,  and  in  those  cases,  which  are 
numerous,  in  which  the  clinical  symptoms  are  atypical,  the  diagnosis  must  rest 
upon  the  result  of  a  blood  examination.  The  therapeutic  test  by  the  adminis- 
tration of  quinine,  urged  by  some  writers,  is  unsatisfactory,  for  while  the  fever, 
if  malarial,  will  succumb  to  the  drug,  there  is  no  surety  that  malaria  was  the 
disease  present,  for  every  fever  which  declines  after  the  administration  of  this 
drug  is  not  malarial  in  nature.  Our  vital  statistics  are  burdened  with  hundreds 
of  cases  of  fevers  diagnosed  as  malarial  because  quinine  reduced  them  or  they 
disappeared  spontaneously,  and  it  is  evident  that  we  can  never  be  sure  of  the 
variety  of  malaria  present  when  we  employ  quinine  as  a  diagnostic  aid  to  the 
exclusion  of  the  blood  examination.     Again,  the  continued  use  of  quinine  is 

307 


308       DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 

often  injurious  to  the  patient,  as  has  been  noted  in  the  discussion  of  typho- 
malarial  fever,  and  to  keep  a  typhoid  patient  cinchonized  for  weeks,  under  the 
impression  that  the  fever  is  due  to  malaria,  when  a  few  moments'  examination 
of  the  blood  would  definitely  decide  the  question,  is  hardly  less  than 
criminal. 

As  a  rule,  one  examination  of  the  blood,  if  carefully  made,  will  be  found 
sufficient ;  but  if .  a  negative  result  is  obtained  in  a  suspected  case,  repeated 
examinations  should  be  made  at  intervals,  for  in  some  cases  so  few  plasmodia 
are  present  in  the  blood  that  such  repeated  examinations  are  necessary  in  order 
to  demonstrate  them.  The  statement  so  often  made  that  cases  of  malaria  occur 
in  which  it  is  impossible  to  demonstrate  plasmodia  in  the  blood,  while  it  may  be 
true,  has  not  proven  so  in  my  experience.  From  personal  observation,  I  believe 
that  such  cases  must  be  very,  very  rare  and  so  mild  in  character  that  it  would 
be  impossible  to  recognize  them  clinically.  I  have  yet  to  observe  a  case  of 
malarial  fever  severe  enough  to  cause  clinical  symptoms  in  which  it  was  im- 
possible to  demonstrate  plasmodia  in  the  peripheral  blood,  if  repeated  examina- 
tions were  made.  On  the  other  hand,  I  have  records  of  hundreds  of  cases  of 
very  mild  and  latent  infections,  in  which  plasmodia  were  found  in  the  per- 
ipheral blood. 

The  general  factors  to  be  considered  in  arriving  at  a  suppositional  diagnosis 
of  malaria  are  the  following:  The  season  of  the  year;  the  locality,  as  to  whether 
it  is  malarious;  the  location  of  the  dwelling  of  the  patient;  the  history  of  previous 
attacks  of  fever;  the  presence  of  Anophelinae;  the  periodicity  of  the  fever;  the 
chances  of  infection;  the  age  of  the  patient,  if  we  are  dealing  with  natives  of  the 
tropics;  the  presence  of  the  signs  of  malaria  cachexia  or  of  anaemia;  and  the 
occurrence  of  similar  fevers  in  other  members  of  the  household. 

The  microscopical  diagnosis  of  the  malarial  fevers  depends  upon  the  find- 
ing of  the  plasmodia  in  the  blood  or  the  presence  in  the  same  fluid  of  pigmented 
leucocytes.  The  finding  of  free  pigment  is  also  conclusive  of  malarial  infection, 
past  or  present,  but  it  is  often  impossible  to  distinguish  such  pigment  from 
extraneous  substances,  and  a  diagnosis  based  upon  the  presence  of  free  pig- 
ment alone  is  always  open  to  question.  The  endeavor  to  diagnose  malaria  by 
a  differential  blood  count  has  not  resulted  in  success,  as  a  similar  differential 
count  is  found  in  other  acute  fevers. 

The  Examination  of  the  Blood. 

The  blood  may  be  examined  in  the  fresh  condition  or  various  staining 
methods  may  be  employed  which  render  the  plasmodia  easier  of  detection  than 
they  are  in  fresh  preparations.  Where  it  is  desired  to  study  the  movements  and 
vital  phenomena  of  the  plasmodia  the  use  of  fresh  preparations  is  necessary,  but 
since  the  development  of  the  Romanowsky  staining  method  and  its  modifications, 
the  examination  of  stained  specimens  is  far  better  in  diagnosis,  both  because  the 
plasmodia  are  more  easily  seen  and  because  there  is  less  chance  of  mistaking 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       309 

other  objects  for  them.  The  use  of  one  of  the  chromatin  stains  is  also  neces- 
sary when  we  desire  to  study  the  exact  structure  of  the  malarial  plasmodia. 

Apparatus. — The  apparatus  necessary  in  making  a  blood  examination  for 
malaria  is  very  simple  and  can  easily  be  transported  to  the  bedside  of  the 
patient,  if  that  be  necessary.  A  good  compound  microscope,  with  a  1/12  inch 
oil  immersion  lens;  microscopic  cover-glasses  and  slides;  two  or  three  medicine 
droppers;  a  bottle  of  staining  solution,  and  a  bottle  of  distilled  water  are  all 
that  is  necessary  to  enable  us  to  make  the  most  exact  examination  of  the  blood 
for  malaria.  The  1/12  oil  immersion  lens  is  absolutely  essential,  for  while  the 
larger  forms  of  the  tertian  and  quartan  plasmodia,  and  the  gametes,  or  crescents, 
of  the  aestivo-autumnal  fevers  may  be  seen  with  a  lens  as  low  as  a  1/6  inch, 
the  small  hyaline  ring-forms  can  only  be  well  seen  when  the  1/12  lens  is  used. 
It  is  a  great  mistake  to  undertake  the  microscopic  diagnosis  of  malaria  without 
a  1/12  inch  oil  immersion  lens.  An  Abbe  condenser  is,  of  course,  an  essential 
portion  of  the  microscope,  and,  if  possible,  the  microscope  should  be  equipped 
with  a  mechanical  stage,  for  the  use  of  such  a  stage  increases  the  chance  of 
finding  the  plasmodia  very  greatly,  and  this  fact,  together  with  the  infinitely 
greater  ease  of  manipulation,  and  the  satisfaction  of  knowing  that  the  same 
portion  of  the  specimen  has  not  been  looked  over  twice,  is  worth  far  more  to  the 
observer  than  the  slight  additional  cost  of  such  a  stage. 

Objects  Which  maybe  Mistaken  for  Plasmodia. — There  is  no  one  thing 
more  essential  to  success  in  recognizing  the  malarial  plasmodia  in  the  blood 
than  a  practical  knowledge  of  the  microscopical  appearance  of  both  fresh  and 
stained  specimens  of  normal  and  pathological  blood.  He  who  supposes  that 
he  has  only  to  look  into  his  microscope  at  a  specimen  of  blood  in  order  to  find 
the  plasmodia,  without  having  had  previous  experience  in  blood  examinations, 
will  invariably  be  disappointed,  and  will  either  give  up  the  search  in  disgust  or 
mistake  some  artefact  or  other  object  for  the  malarial  plasmodium.  Success 
might  possibly  attend  the  search  of  such  a  tyro  in  the  case  of  the  large,  fully 
developed  forms  of  the  quartan  or  tertian  plasmodium,  but  never  when  the 
hyaline  "ring-forms"  of  the  aestivo-autumnal  plasmodia  are  alone  present. 
The  use  of  a  good  chromatin  stain  has  done  much  to  enable  the  less  experi- 
enced observer  to  recognize  these  organisms,  and  for  this  reason  the  use  of 
stained  specimens  in  diagnosis  is  preferable  to  the  examination  of  the  fresh 
blood. 

In  fresh  specimens  of  blood  the  following  objects  may  be  mistaken  for 
malarial  plasmodia: 

Crenations. — These  occur  if  the  blood  be  exposed  long  to  the  air  in  mak- 
ing ;the  specimen  or  if  the  slide  or  cover-glass  be  not  clean,  and  are  confusing 
to  an  inexperienced  observer  if  they  be  looked  down  upon  directly,  as  they  thus 
appear  as  round,  rather  haline  bodies  within  the  red  corpuscles,  but  they  have  no 
ring-like  outline,  and  when  focussed  upon  appear  alternately  as  light  and  dark 
areas. 

Retraction  of  the  haemoglobin  from  the  edge  of  the  red  cell  is  often 


3IO       DL\GXOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 

observed  at  some  point  on  the  periphery  of  the  cell,  giving  rise  to  small  areas 
devoid  of  haemoglobin,  but  they  have  no  amoeboid  motion,  and  when  focussed 
upon  often  present  a  reddish  refraction  about  the  edge.  Cracks  in  the  haemo- 
globin are  similar  in  appearance  and  are  generally  easily  differentiated  from 
Plasmodia. 

Vacuoles. — There  is  no  more  deceiving  object  in  the  blood  than  a  small 
vacuole  within  the  red  corpuscle.  Sometimes,  especially  if  the  border  of  the 
vacuole  alters  in  shape,  the  resemblance  to  the  hyaline  disk-form  of  the  aestivo- 
autumnal  plasmodia  is  well-nigh  perfect.  I  have  time  and  again  had  such 
vacuoles  shown  to  me  for  plasmodia  by  experienced  microscopists  who  had 
had  but  little  practice  with  malarial  blood.  The  greater  refraction  of  the 
vacuole,  its  less  opaque  character,  and  the  fact  that  vacuoles  "open  out"  or 
grow  larger  and  smaller  as  focussed  upon,  should  distinguish  them  from  any 
of  the  stages  of  growth  of  the  malarial  plasmodia. 

Areas  devoid  of  haemoglobin  or  "eye  spots"  as  they  have  been  termed 
by  some  observers,  occur  within  the  red  cells  frequently  in  diseases,  such  as 
typhoid  fever,  tuberculosis,  pneumonia,  and  the  acute  infectious  diseases, 
and  are  also  observed  in  normal  blood.  They  may  be  situated  at  any  portion 
of  the  corpuscle,  and  may  be  round,  spindle-shaped,  oval,  or  ring-shaped,  and 
hyaline  in  appearance.  Many  of  them,  especially  the  oval  and  spindle-shaped 
areas  contain  a  darker  dot  at  the  center,  which  resembles  pigment.  These 
bodies  have  been  several  times  described  as  new  parasites  and  sometimes  their 
superficial  resemblance  to  the  ring-forms  of  the  malarial  plasmodia  is  striking, 
but  the  absence  of  ameboid  movements,  and  the  much  greater  degree  of  refrac- 
tion should  serve  to  differentiate  them  from  the  plasmodia. 

Platelets. — Occasionally  a  blood  platelet,  if  superimposed  upon  a  red 
blood-corpuscle,  will  resemble  slightly  a  malarial  plasmodium,  but  upon 
focussing  it  will  be  observed  that  there  is  a  great  difference  in  the  level  of  the 
two  objects  and  that  the  platelet  is  less  opaque  and  less  refractive  than  the 
malarial  plasmodia. 

Haemokonien  or  blood-dust  may  sometimes  be  mistaken  for  plasmodia, 
especially  when  the  small  active  granules  lodge  upon  a  red  cell,  but  a  little 
practice  will  soon  suffice  to  differentiate  these  bodies. 

Granules  derived  from  broken-down  leucocytes  sometimes  resemble  small 
plasmodia  when  they  rest  upon  the  red  corpuscles,  but  their  size,  the  absence 
of  amoeboid  motion  and  their  less  hyaline  appearance  easily  serve  to  distinguish 
them. 

Other  objects  which  may  cause  trouble  to  the  beginner  are  grains  of  dirt 
which  may  be  mistaken  for  pigment;  the  normal  lighter  colored  center  of  the 
red  corpuscles,  especially  marked  in  persons  suffering  from  anaemia;  cocci  or 
bacteria  in  the  blood;  and  flaws  or  dirt  upon  the  slide  or  cover-glass. 

In  stained  specimens  the  objects  most  apt  to  be  mistaken  for  plasmodia 
are  the  blood  plates,  especially  when,  as  often  occurs,  they  are  observed  with 
the  red  corpuscles.     They  may  be  distinguished  by  their  smaller  size  (as  a  rule) 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       3II 

and  the  minuteness  of  their  chromatin  granules,  as  well  as  the  absence  of  the 
distinct  blue  protoplasm  observed  in  the  malarial  plasmotlia. 

Bacteria  upon  the  red  cells;  Yeasts,  and  extraneous  matter,  which  may 
be  stained,  are  all  sometimes  mistaken  for  plasmodia,  but  a  very  little  experience 
in  the  examination  of  stained  specimens  of  blood  will  render  such  mistakes 
impossible.  Flaws  upon  the  slide,  in  which  the  stain  may  settle,  sometimes 
resemble  extracellular  plasmodia,  but  careful  examination  will  demonstrate 
their  nature. 

The  flagellated  plasmodia  are  simulated  by  certain  erythrocytes  under- 
going degeneration,  in  which  long,  slender,  active  protoplasmic  pseudopodia 
are  observed  projecting  from  the  periphery  of  the  misshapen  red  cell.'  These 
bodies  may  be  distinguished  from  the  flagellated  plasmodia  by  the  greenish 
color  due  to  the  haemoglobin  of  the  red  cell  and  by  the  absence  of  pigment. 


5678 

Fig.  23. — Appearances  in  the  Red  Blood-corpuscles  which  have  been  mistaken  for  Plasmodia 
1,  Crenations;  2,  Vacuoles;  3,  Areas  devoid  of  haemoglobin;  4,  Blood  plates;  5,  Blood  dust; 
6,  Bacteria  of  various  kinds;  7,  Yeast  cells;  8,  Free  pigment  granules. 


The  crescents  or  gametes  of  the  aestivo-autumnal  plasmodia  are  frequently 
confused  with  folded  red  cells,  which  have  a  crescentic  outline,  but  such  cells 
may  be  easily  differentiated  from  the  plasmodia  by  their  green  color  and  the 
absence  of  pigment. 

Preparation  of  Blood  Specimens. — The  following  procedure  is  recom- 
mended if  it  be  desired  to  procure  fresh  specimens  of  blood  for  examination. 
The  patient's  ear  lobe,  or  the  tip  of  the  finger,  is  carefully  cleaned  with  alcohol, 
dried  thoroughly,  a  slight  puncture  made  with  a  lancet  or  needle,  and  the 
first  drop  or  two  of  blood  allowed  to  flow  away.  A  small  drop  is  then  taken 
upon  a  slide  which  has  been  carefully  cleaned  and  a  cover-glass  dropped  gently 
upon  it.  If  the  cover-glass  is  thin,  and  the  drop  of  blood  on  the  slide  small,  the 
blood  will  spread  evenly  and  quickly,  but  if  it  does  not,  very  slight  pressure  upon 
the  cover-glass  will  suffice  to  spread  the  blood  and  will  do  no  harm.  If  upon 
examination  it  is  found  that  the  blood-cells  are  in  clumps  or  rouleaux,  the  prep- 
aration should  be  discarded  and  one  obtained  in  which  the  red  cells  are  spread 
singly  and  evenly  over  the  field.  The  preparation  of  the  specimen  should  take 
as  little  time  as  possible,  as  exposure  of  the  blood  to  the  air  crenates  the  red  cells 
and  thus  renders  it  difficult  to  find  the  plasmodia.     A  little  practice  will  enable 


312       DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 

one  to  secure  suitable  specimens  very  quickly.  The  specimens  should  be 
examined  as  soon  as  possible,  but  if  carefully  wrapped  in  tissue-paper  can  be 
carried  in  the  pocket  for  several  hours  without  much  danger  of  changes  occurring 
which  will  obscure  the  plasmodia,  and  if  the  specimens  be  ringed  with  vaseline 
they  will  keep  well  for  as  long  as  twelve  hours.  The  ear  is  preferable  to  the 
finger  for  obtaining  the  blood,  especially  in  children,  as  there  is  less  pain,  and 
the  patient  cannot  watch  the  operator  during  the  procedure.  At  least  half  an 
hour  should  be  spent  upon  the  examination  of  the  specimen  before  it  is  considered 
negative,  and  more  than  one  specimen  should  be  examined  when  a  negative 
result  is  obtained.  For  the  examination  of  certain  phenomena  in  the  life 
cycle  of  the  malarial  plasmodia,  such  as  exflagellation,  the  use  of  fresh  specimens 
of  blood  is  essential,  but  with  our  improved  methods  of  staining,  better  results 
in  diagnosis  will  be  arrived  at,  by  the  majority  of  physicians,  if  stained  specimens 
be  used,  provided  some  practice  has  been  had  in  distinguishing  these  organisms 
in  such  preparations. 

Preparation  of  Stained  Specimens. — The  preparation  of  blood  smears 
for  staining  is  so  simple  that  it  is  remarkable  to  read  in  many  of  our  works 
upon  diagnosis  the  elaborate  methods  advocated  for  making  blood  smears,  some 
of  them  involving  the  use  of  special  apparatus.  All  that  is  necessary  in  the 
way  of  apparatus  are  two  microscopic  slides  and  a  needle  with  which  to  make 
the  puncture  in  the  ear  or  finger.  After  washing  the  ear  as  described  and 
allowing  a  drop  or  two  of  the  blood  to  flow  away,  a  small  drop  is  caught  upon 
the  end  of  one  slide  and  the  edge  of  the  other  slide  applied  to  it,  when  the  blood 
will  spread  along  the  applied  edge.  As  soon  as  this  occurs,  draw  the  edge 
of  the  slide  gently  along  the  surface  of  the  slide  upon  which  is  the  drop  of  blood, 
and  a  thin  even  smear  will  result.  This  is  allowed  to  dry  and  is  then  ready  for 
staining.  Good  smears  may  be  obtained  by  spreading  the  blood  over  the  slide 
with  the  needle,  but  the  smears  so  obtained  are  apt  to  be  thicker  than  when 
the  edge  of  the  slide  is  used. 

Staining  Methods.— Many  methods  have  been  devised  for  staining  the 
plasmodia  of  malaria,  but  prior  to  the  description  in  1890,  by  Romanowsky,  of 
his  staining  method,  the  results  obtained  were  unsatisfactory  from  a  diagnostic 
standpoint  as  well  as  from  a  morphological  one.  In  Romanowsky's  method, 
however,  the  staining  reactions  of  the  plasmodia  were  so  distinctive  that  they 
could  hardly  be  mistaken  for  other  objects,  and  thus  the  method  was  generally 
adopted  in  the  diagnosis  of  the  parasites  of  malaria.  Various  modifications  of 
the  method  have  been  evolved,  many  of  them  superior  to  the  original  and 
easier  of  application.  The  success  of  the  Romanowsky  stain  and  all  of  its 
modifications  depends  upon  the  fact  that  when  a  solution  of  methylene  blue  is 
acted  upon  by  sodium  carbonate  or  some  other  alkaline  reagent,  methylene 
azure  and  methylene  violet  result,  being  formed  in  the  solution.  When  these 
bodies  are  in  turn  acted  upon  by  a  solution  of  eosin,  certain  bodies  result  which 
have  the  power  of  staining  the  nuclear  chromatin  an  intense  red,  hence  the 
name  "chromatin  stains"  applied  to  these  staining  methods.     In  old  poly- 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       313 

chrome  methylene  blue  solutions  these  staining  bodies  are  present,  but  they  can 
be  quickly  produced  in  fresh  solutions  if  certain  procedures  are  followed.  I 
shall  describe  here  only  those  staining  methods  which  I  have  personally  found 
satisfactory,  merely  mentioning  those  which  have  been  used  by  various  ob- 
servers, but  which  have  not  proven  generally  useful. 

Wright's  Stain. — In  my  own  work  I  have  found  Wright's  stain,  as  modified 
by  Oliver,  most  satisfactory,  and  at  the  present  time  I  use  this  stain  to  the  ex- 
clusion of  all  others.  In  over  10  years'  experience  I  have  always  found  this 
stain  reliable  when  properly  made  and  when  the  right  ingredients  were 
used.  It  should  be  remembered  that  this  stain  depends  for  its  efficiency  upon 
chemically  pure  ingredients  and  the  substitution  of  others  will  always  result  in 
disappointment. 

Chemicals  Used  in  Preparation  of  Wright's  Stain. — The  following 
chemicals  are  used  in  preparing  Wright's  stain:  1.  Methylene  blue  (Grubler'sj. 
2.  Eosin.  Yellow.  Water  soluble  (Grubler's).  3.  Methylic  alcohol  (Merck's 
reagent). 

Method  of  Preparation. — The  stain  I  use  is  prepared  as  follows:  Add 
0.5  gm.  of  sodium  bicarbonate  to  100  c.c.  of  distilled  water,  dissolve  thoroughly, 
and  add  1  gm.  of  methylene  blue  (Grubler);  heat  the  mixture  for  one  hour  in 
an  Arnold  sterilizer  or  other  steam  sterilizer,  after  the  steam  is  up.  After  heat- 
ing allow  the  solution  to  cool.  Make  a  1  to  1,000  solution  of  yellow  aqueous 
eosin  (Grubler)  and  add  this,  while  stirring,  to  the  cooled  mythylene  blue 
solution,  in  about  the  proportion  of  500  c.c.  of  the  eosin  solution  to  75  c.c.  of  the 
methylene  blue  solution.  This  should  be  done  in  a  white  dish  of  some  kind, 
in  order  that  the  precipitate  that  forms  as  the  eosin  solution  is  added  may  be 
easily  seen.  The  proportion  of  eosin  solution  added  to  the  methylene  blue 
solution  will  vary  in  different  batches  of  the  stain,  but  the  eosin  solution  should 
always  be  added  until  a  well-marked  precipitate  follows  after  stirring.  A  marked 
metallic  scum  will  appear  upon  the  surface  of  the  mixture  at  the  time  the  eosin 
solution  is  in  sufficient  quantity  and  this  may  be  used  as  an  indicator,  but  if  no 
precipitate  is  present  when  the  metallic  scum  appears  the  eosin  solution  should 
be  added  until  it  appears.  The  mixture  should  then  be  allowed  to  stand  for 
fifteen  or  twenty  minutes,  and  then  filtered  through  one  small  filter-paper,  the 
precipitate  saved,  dried  in  a  hot-air  oven,  removed  from  the  filter-paper,  and 
used  in  making  the  staining  solution.  The  precipitate,  which  is  a  fine  powder, 
greenish  in  color,  will  keep  well  and  can  be  used  as  stock  material  for  months. 

The  staining  solution  is  prepared  as  follows:  Take  0.3  gm.  of  the  powdered 
precipitate  and  add  it  to  100  c.c.  of  pure  methylic  alcohol  (Merck's  reagent), 
filter,  and  to  80  c.c.  of  the  filtrate  add  20  c.c.  of  the  methylic  alcohol,  or  if  more 
than  80  c.c.  be  left  after  filtration,  enough  to  bring  the  entire  amount  up  to 
100  c  c.  The  staining  solution  is  now  ready  for  use  and  will  keep  unim- 
paired for  weeks. 

Method  of  Use. — To  stain,  add  a  few  drops  of  the  staining  solution  to  the 
blood  smear  prepared  in  the  manner  directed,  and  let  stand  for  from  two  to  four 


314       DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 

minutes.  This  fixes  the  specimen.  Then  add  enough  distilled  water  to  cause 
a  slight  metallic  scum  to  form  upon  the  surface  of  the  preparation;  let  stand  for 
from  three  to  five  minutes,  wash  in  running  distilled  water,  and  examine  when 
dry.  The  washing  in  distilled  water  is  important,  as  by  it  the  precipitate  formed 
during  the  staining  process  is  removed,  and  it  should  be  continued  until  the 
specimen  is  a  delicate  shade  of  pink  or  pinkish-brown.  If  it  is  desired  to  pre- 
serve  the  specimen,  do  not  mount  in  Canada  balsam,  but  preserve  the  slide 
without  the  addition  of  a  cover-glass. 

Prepared  and  used  in  the  manner  described,  it  will  be  found  that  Wright's 
stain  is  always  reliable  and  can  be  depended  upon  to  give  the  most  beautiful 
pictures  of  stained  malarial  plasmodia.  1  have  had  but  little  success  with  this 
stain  as  prepared  by  manufacturing  chemists,  and  would  strongly  advise  that 
the  stain  be  made  by  the  one  using  it,  and  that  only  the  ingredients  mentioned 
be  used  in  its  manufacture.  None  of  the  other  modifications  of  Romanowsky's 
stain,  such  as  Leishman's,  Nocht's  or  Jenner's  can  compare  with  this  stain,  in 
my  opinion,  as  regards  ease  of  manipulation  and  the  results  obtained. 

The  Staining  Reactions  of  the  Blood  With  Wright's  Stain. — In 
specimens  of  blood  properly  stained  with  Wright's  stain,  the  red  blood-corpus- 
cles are  stained  a  brownish-pink  or  a  light  pink,  while  the  various  leucocytes 
are  stained  as  follows:  the  polynuclear  leucocytes  present  a  light  red  nucleus 
with  unstained  protoplasm  except  for  light  pink  granules  which  are  generally 
present  within  the  protoplasm;  the  mononuclears  and  lymphocytes  have  a  dark 
ruby-red  or  violet  nucleus,  very  sharply  defined,  while  the  protoplasm  is  stained 
a  light  blue;  the  eosinophiles  have  a  deep  violet  nucleus  and  the  granules  are 
stained  a  pale  red,  in  the  coarsely  granular  variety,  a  brilliant  red;  the  mast  cells 
have  dark  purplish-black  granules,  and  a  dark  red  nucleus;  the  blood  plates 
stain  a  bright  ruby-red,  with,  in  most  instances,  a  well  marked,  pale  lilac  margin. 

The  staining  reactions  of  the  malarial  plasmodia  when  Wright's  stain  is 
used  have  already  been  thoroughly  described  in  the  section  dealing  with  the 
morphology  of  the  plasmodia.  It  may  be  repeated  here,  however,  that  the 
protoplasm  of  the  plasmodia  stains  a  robin's  egg-blue,  the  vesicular  portion  of 
the  nucleus  remains  unstained,  while  the  chromatin  of  the  nucleus  stains  a 
beautiful  ruby-red. 

Other  Methods  of  Staining  the  Malarial  Plasmodia. — Among  the 
other  methods  in  use  for  staining  the  malarial  plasmodia  the  following  are  the 
most  important  and  useful: 

Romanowsky's  Method. — Two  solutions  are  used:  Sol.  1.  Methylene  blue 
(Grubler),  1  part.  Sodium  carbonate,  1.5  part.  Water,  100  parts.  Sol.  2. 
Eosin,  yellow  aqueous  (Grubler)  1  part.  Water,  1000  parts.  Solution  1 
should  be  mixed  and  kept  in  an  incubator  for  several  days  or  in  the  sun-light, 
until  a  distinct  purple  tinge  develops,  and  solution  2  should  be  kept  in  the  dark. 

The  staining  solution  is  made  by  mixing  5  c.c.  of  each  solution  with  95  c.c. 
of  water  and  then  adding  the  methylene  blue  solution  to  the  eosin  solution  in 
the  proportion  of  one  part  of  the  former  to  two  parts  of  the  latter.     The  stain 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       315 

should  be  allowed  to  act  for  at  least  fifteen  minutes  and  the  best  specimens  are 
obtained  after  from  one  to  two  hours.  After  staining,  the  smears  should  be 
thoroughly  washed  in  running  distilled  water.  The  staining  reactions  are 
similar  to  those  obtained  with  the  Wright  stain. 

Leishman's  Method. — This  method  is  a  favorite  one  in  England,  but  I 
have  not  secured  as  good  results  with  it  as  with  Wright's  method,  although 
it  is  an  excellent  stain  for  the  plasmodia.  The  method  of  preparing  this  stain 
is  as  follows. 

1.  Make  a  1  per  cent,  solution  of  Grubler's  medicinal  blue  in  distilled 
water  made  alkalein  by  the  addition  of  0.5  per  cent,  of  sodium  carbonate. 
Heat  for  12  hours  at  650  C.  in  an  oven  and  allow  to  stand  for  10  days  at  room 
temperature  before  using. 

2.  Prepare  a  1  to  1000  solution  of  eosin  (Grubler's  extra  B.  A.). 

3.  Equal  volumes  of  these  two  solutions  are  mixed  in  an  open  dish  and 
allowed  to  stand  for  from  6  to  1 2  hours,  during  which  time  the  mixture  should 
be  stirred  at  intervals. 

4.  Collect  the  precipitate  that  results  upon  one  small  filter-paper  and  wash 
with  distilled  water  until  the  washings  are  colorless  or  a  pale  blue;  the  precipitate 
is  then  dried  and  powdered. 

5.  To  make  the  staining  fluid,  dissolve  0.15  gm.  of  the  powder  in  1,000  c.c. 
of  Merck's  methylic  alcohol  (reagent). 

The  method  of  using  the  staining  solution  is  similar  to  that  of  Wright's,  a 
little  of  the  stain  being  added  to  the  smear,  allowed  to  remain  for  two  to  three 
minutes,  when  distilled  water  is  added  until  a  slight  metallic  scum  appears  upon 
the  surface;  the  specimen  is  then  stained  for  five  more  minutes,  and  washed  in 
running  distilled  water.  After  washing,  Leishman  recommends  that  the  stained 
smears  be  allowed  to  soak  in  distilled  water  for  one  minute,  claiming  that  this 
intensifies  the  chromatin  stain,  removes  deposits,  and  changes  the  color  of  the 
red  blood-corpuscles  to  a  delicate  pink.  If  this  be  done  the  smears  will  be 
free  from  any  precipitate.  The  staining  reactions  are  the  same  as  with  Wright's 
stain. 

Nocht's  Method. — The  following  method,  advocated  by  Nocht,  is  said 
by  Ewing  to  be  excellent  for  staining  the  malarial  plasmodia,  but  I  have  not 
found  it  as  satisfactory  as  Wright's  stain.     The  following  solutions  are  used: 

1.  To  30  c.c.  of  polychrome  methylene  blue  (Grubler)  add  five  drops  of  a 
3  per  cent,  solution  of  acetic  acid  (U.  S.  P.,  23  Per  cent.). 

2.  Make  a  saturated  solution  of  methylene  blue  (Grubler)  dissolving  the 
powder  by  gentle  heat  in  water.  This  solution  should  be  kept  for  at  least 
a  week  before  it  is  used. 

3.  Make  a  1  per  cent,  solution  in  water  of  yellow  aqueous  eosin  (Grubler). 
The  staining  solution  is  prepared  as  follows: 

To  10  c.c.  of  water  add  four  drops  of  the  eosin  solution,  six  drops  of  the 
polychrome  methylene  blue,  and  2  drops  of  the  1  per  cent,  methylene  blue 
solution,  mixing  well. 


6 


1 6       DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 


The  stain  is  used  as  follows: 

The  blood  smears  are  fixed  by  absolute  alcohol  for  five  minutes  or  by  heat, 
stained  for  two  hours  or  more  with  the  staining  solution,  in  a  moist  chamber, 
washed  in  distilled  water,  and  examined.  The  best  result  is  obtained  after  six 
or  more  hours'  staining. 

According  to  Nocht,  the  two  methylene  blue  solutions  may  be  replaced  by 
a  i  per  cent,  solution  of  Ehrlich's  rectified  methylene  blue  to  which  has  been 
added  a  few  drops  of  a  half  of  i  per  cent,  solution  of  sodium  hydrate,  the 
mixture  having  been  heated  for  a  few  days  in  an  incubator  at  500  C.  When 
this  solution  is  used  the  method  of  staining  consists  in  adding  two  or  three 
drops  of  the  eosin  solution  to  2  c.c.  of  water,  and  to  this  adding,  drop  by  drop, 
the  methylene  blue  solution,  until  the  red  color  of  the  eosin  solution  had  nearly 
disappeared.  The  results  are  not  as  good  as  when  the  original  method  is  used. 
With  this  stain  the  staining  reactions  are  similar  to  those  obtained  by  Wright's 
stain. 

Plehn's  Method. — The  following  method,  advocated  by  Plehn,  is  some- 
times useful,  but  the  chromatin  staining  is  uncertain. 

The  following  solution  is  used: 

Concentrated  aqueous  solution  of  methylene  blue  (Grubler),  60  parts. 

One-half  per  cent.  sol.  of  eosin  in  75  per  cent,  alcohol,  20  parts. 

Distilled  water,  40  parts. 

Twenty  per  cent,  solution  of  sodium  hydrate,  12  drops. 

The  blood  smears  are  fixed  in  absolute  alcohol  for  five  minutes,  stained  in 
the  above  solution  for  from  five  to  ten  minutes,  washed  in  water,  and  examined. 
Marino's  Stain. — This  stain,  somewhat  more  complicated  in  technic 
than  Wright's,  but  which  gives  excellent  results  when  carefully  prepared  and 
used,  is  as  follows: 

Sol.  I.  Methylene  blue  (Grubler's),  0.5  gm. 

Azure  blue,  0.5  gm. 

Water,  100.0  c.c. 

Sodium  bicarbonate,  0.5  per  cent,  sol.,      10. o  c.c. 

This  solution  is  kept  in  the  incubator  at  730  C.  for  from  two  to  four  daysj 
or  heated  to  6o°  C.  for  six  hours. 

Sol.  II.  A  0.2  per  cent,  solution  of  aqueous  eosin  (Grubler's).  The 
eosin  solution  is  added  to  the  methylene  blue  solution  until  a  well-marked 
precipitate  occurs,  which  is  collected  by  filtration,  dried,  and  used  as  stock 
material. 

The  staining  solution  is  made  by  adding  0.4  gm.  of  the  methylene-azure 
powder,  obtained  by  filtration,  to  20  c.c.  of  pure  methylic  alcohol,  and  is  used 
as  follows: 

The  blood  smears  are  covered  with  the  staining  solution,  the  number  of 
drops  required  to  do  so  being  recorded.     After  the  stain  has  been  allowed 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       3  I  7 

to  act  for  three  or  four  minutes,  double  the  number  of  drops  of  an  aqueous 
solution  of  eosin,  containing  0.05  gm.  of  eosin  to  1,000  c.c.  of  water  are  added, 
and  left  on  for  from  two  to  three  minutes.  The  smears  are  then  thoroughly 
washed  in  distilled  water  and  examined  at  once. 

Giemsa's  Stain. — This  stain,  so  useful  in  staining  Treponema  pallidum 
and  Treponema  pertenuis,  is  also  a  valuable  stain  for  the  plasmodia  of  malaria, 
but  its  method  of  preparation  is  so  complicated  and  requires  so  much  care  that, 
while  the  results  obtained  by  it  are  reliable,  it  is  not  as  available  for  general  use 
as  is  the  more  simple  Wright's  method.  It  is  also  very  prone  to  overstain  and 
to  undergo  changes  with  age  which  render  it  useless  for  the  staining  of  the 
malarial  parasites.     The  stain  is  prepared  as  follows: 

In  preparing  the  stain  and  using  it  the  utmost  care  should  be  taken  that 
everything  is  chemically  clean  and  that  none  of  the  dishes  or  implements  used 
are  moist,  and  that  they  are  absolutely  free  from  acid.  The  dishes  should  all 
be  sterilized  before  using  and  thus  rendered  free  from  bacterial  contamination. 

Preparation  of  Stock  Staining  Solution.— Weigh  out  the  following: 

Azure    II-eosin,        3.0  grams. 
Azure    II,  0.8  gram. 

Dissolve  these,  with  constant  shaking,  in  chemically  pure  glycerine  (250  c.c.) 
at  a  temperature  of  6o°  C.  After  solution  is  complete  add  250  c.c.  of  absolute 
methyl  alcohol  (Kaulbaum  I)  previously  heated  to  6o°  C.  This  mixture  is 
shaken  well,  allowed  to  stand  at  room  temperature  for  24  hours,  and  then 
filtered  into  a  chemically  clean,  sterilized  air-tight  stock  bottle.  During  the 
filtration  the  funnel  must  be  covered  with  an  inverted  watch-glass  to  protect 
the  hydroscopic  fluid  from  moisture. 

The  stain  should  always  be  protected  from  the  sunlight. 

The  method  of  using  this  stain  is  as  follows: 

For  structures  such  as  spirochaetes,  the  Treponema,  and  the  malarial 
plasmodia  proceed  as  follows: 

1.  Make  thin,  even  smears  of  the  material  to  be  examined  upon  fat-free 
cover-slips  or  slides. 

2.  Dry  in  the  air  and  fix  for  twenty  minutes  in  absolute  ethyl  alcohol. 

3.  Blot  off  the  alcohol  with  smooth,  closely  woven,  white  filter-paper. 

4.  Stain  with  the  following  solution: 

Stock  solution,     10  drops 
Distilled  water,   10  c.c. 

One  per  cent.  sol.  potass,  carb.  1  or  2  drops  to  each  10  c.c.  of  the  mixture 
of  distilled  water  and  stock  solution. 

If  the  malarial  plasmodia  are  to  be  stained,  the  staining  solution  should  be 
allowed  to  act  for  from  5  to  10  minutes,  but  if  the  treponema  is  to  be  stained  it 
should  be  at  least  an  hour  before  the  stain  is  removed. 

5.  Wash  the  stained  smears  in  running  distilled  water,  air  dry,  and  examine 


318       DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 

at  once.  With  this  stain  the  protoplasm  of  the  plasmodium  colors  a  very  dark 
blue,  the  vesicular  part  of  the  nucleus  remains  unstained,  and  the  chromatin 
takes  a  very  dark  red,  almost  black  color. 

Staining  of  Flagellated  Parasites.— The  flagellated  forms  of  the  mala- 
rial plasmodia  may  be  stained  by  any  of  the  methods  mentioned,  Wright's 
stain  being  especially  serviceable.  A  patient  should  be  selected  in  which 
gametes  are  numerous,  and  the  blood  should  be  exposed  a  short  time  to  the  air 
after  securing  it  on  the  slide,  or  the  slide  may  be  breathed  upon  to  hasten 
exflagellation.  The  smear  should  be  thick  and  should  be  allowed  to  dry 
slowly.  The  technic  of  staining  is  the  same  as  for  the  other  forms  of  plasmo- 
dia, but  it  is  well  to  allow  the  stain  to  act  longer  after  the  water  has  been  added. 

Bodies  in  Stained  Specimens  Which  may  be  Mistaken  for  Plasmodia. 
— To  one  who  has  had  much  experience  in  the  examination  of  stained  specimens 
of  malarial  blood,  where  any  of  the  chromatin  stains  have  been  used,  the  mistake 
of  confusing  any  stage  of  growth  of  the  plasmodia  with  artefacts,  granules  of 
dirt,  or  other  objects,  is  impossible,  for  the  staining  reactions  of  the  plasmodia 
are  very  distinctive,  and  a  comparatively  little  practice  will  enable  one  to 
recognize  the  stained  organisms  without  any  difficulty.  Certain  objects  may  be 
mistaken  in  stained  specimens  for  plasmodia  by  those  unused  to  studying  such 
preparations,  the  most  important  of  which  are  the  following: 

i.  Flaws  in  the  slide  in  which  a  portion  of  the  stain  may  collect.  If  these 
be  situated  beneath  a  red  blood-corpuscle  they  may  resemble  a  poorly  stained 
Plasmodium,  but  upon  focussing  it  will  be  observed  that  they  are  situated  at  a 
different  level  than  the  red  cell  and  thus  they  may  be  easily  distinguished. 

2.  Blood  platelets,  especially  if  lying  upon  the  red  blood-corpuscles,  as 
frequently  happens,  are  commonly  mistaken  for  plasmodia  by  those  unaccus- 
tomed to  stained  preparations.  They  are  differentiated  by  the  lack  of  a  blue- 
stained  protoplasm  and  the  bright  ruby-red  mass  of  chromatin,  the  chromatin 
of  the  blood  plate  being  darker  in  color,  irregular  in  outline,  and  more  granular 
in  appearance.  Most  blood  plates  are  surrounded  by  a  well-marked  bluish 
limiting  membrane,  especially  well  observed  when  the  plate  is  lying  free  in  the 
plasma.  Sometimes  the  blood  plates  are  collected  in  crescentic  masses  and 
might  be  mistaken  for  crescents,  but  a  little  study  should  served  to  obviate  such 
mistakes. 

3.  Vacuoles,  in  which  some  of  the  stain  has  been  retained,  may  occur  in 
the  red  blood-cells,  but  may  be  easily  distinguished  from  the  plasmodia  by  the 
absence  of  the  blue  protoplasm  and  the  red  chromatin. 

4.  Leucocytes  have  been  mistaken  for  stained  malarial  plasmodia,  but  such 
a  mistake  could  only  be  made  by  the  merest  tyro  in  blood  examinations. 
Among  other  objects  which  might  be  confused  with  the  plasmodia  in  stained 
specimens  may  be  mentioned  particles  of  dirt  of  extraneous  origin,  yeast  cells 
and  other  micro-organisms,  degenerated  leucocytes,  neucleated  red  cells,  and 
basophilia  of  the  red  corpuscle.  It  is  obvious  that  an  acquaintance  with  the 
appearance  of  both  normal  and  diseased  blood  in  stained  specimens  will  make 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       3IQ 

such  mistakes  impossible,  and,  as  I  have  stated,  a  knowledge  of  the  micro- 
scopic appearance  of  normal  blood,  in  both  fresh  and  stained  preparations,  is 
absolutely  essential  to  one  who  expects  to  study  the  malarial  plasmodia  or  to 
make  microscopic  examinations  of  blood  for  diagnostic  purposes. 

The  Microscopic  Diagnosis  of  the  Species  of  Malarial  Plasmodia. — 
The  species  of  malarial  plasmodia  may  be  differentiated  in  both  fresh  and 
stained  specimens  of  blood,  and  in  making  such  a  differentiation  two  factors 
should  be  borne  in  mind,  i.e.,  the  character  of  the  infected  red  corpuscle  and  the 
character  of  the  parasite  infecting  it.  I  have  already  described  in  detail  the 
characteristics  of  the  various  species  of  plasmodia  and  the  changes  occurring 
in  the  infected  red  cell  in  the  chapter  dealing  with  the  morphology  of  the  plasmo- 
dia, but  for  convenience  I  shall  here  give  a  brief  summary  of  the  distinctive 
features  of  the  plasmodia  which  may  be  used  in  diagnosing  the  species  present 
in  any  given  case. 

Tertian  Plasmodium. — The  red  cell  infected  with  Plasmodium  vivax  is 
invariably  enlarged,  even  during  the  earliest  stage  of  growth  of  the  parasite,  and 
after  the  occurrence  of  pigment  the  red  cell  is  markedly  larger  than  the  unin- 
fected cells  and  is  lighter  green  in  color.  The  occurrence  of  Schuffner's  dots  is 
characteristic  of  tertian  infection.  The  youngest  "ring-forms"  are  larger,  more 
veil-like  in  appearance,  and  more  noticeably  amoeboid  than  are  the  "ring- 
forms"  of  any  other  species.  The  pigment  when  developed  is  in  finer,  lighter 
brown  granules  than  in  the  other  species,  and  is  much  more  actively  motile. 
The  organism  after  the  development  of  pigment  and  until  within  a  few  hours  of 
segmentation  is  actively  amoeboid,  thus  leading  to  an  irregularity  in  shape  that 
is  characteristic.  When  fully  developed  the  organism  fills  the  entire  red  cell, 
which  is  greatly  enlarged,  often  twice  to  three  times  the  size  of  a  normal  red  cell. 

In  stained  specimens  the  youngest  tertian  "rings"  are  with  difficulty  dis- 
tinguished from  those  of  other  species,  but  with  the  development  of  pigment, 
the  larger  size  of  the  red  cell  and  the  irregular  shape  of  the  organism  serves  to 
distinguish  it  from  the  other  species.  At  all  stages  it  is  larger  than  any  of  the 
other  plasmodia  at  a  corresponding  stage,  and  the  pigment  is  distributed  through- 
out the  protoplasm  instead  of  collected  in  clumps  as  in  the  other  species. 

Quartan  Plasmodium. — The  infected  red  cell  in  quartan  infection,  or 
infection  with  Plasmodium  malariae,  is  unchanged  or  slightly  smaller  than 
normal  and  slightly  more  greenish  in  color.  The  young  "rings"  are  smaller 
than  the  tertian  "rings,"  more  refractive,  regular  in  shape,  and  generally 
contain  a  little  pigment.  The  larger  forms  are  more  refractive,  regular  in 
shape,  being  oval  or  spherical,  and  the  pigment  is  in  larger,  darker  brown 
granules  than  in  the  tertian  plasmodium,  and  is  collected  about  the  periphery  of 
the  organism.  The  segments  number  from  8  to  12,  while  in  the  tertian  form  the 
segments  number  from  12  to  24.  At  no  stage  of  development  is  the  infected 
cell  enlarged. 

In  stained  specimens  this  species  is  distinguished  by  the  non-enlargement 
of  the  red  cell,  the  fact  that  when  fully  developed  the  organism  fills  the  entire 


320       DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 

cell;  the  character  of  the  pigment;  the  more  deeply  staining  chromatin,  which 
is  present  in  larger  amount;  and  the  number  of  the  segments.  The  absence  of 
Schuffner's  dots  is  also  a  distinguishing  point. 

The  Aestivo-autumnal  Plasmodl^. — The  red  cells  infected  with 
Plasmodium  falciparum  and  Plasmodium  falciparum  quotidianum  are  always 
smaller  than  the  uninfected  red  cells,  and  much  darker  green  in  color.  In 
infections  with  these  plasmodia  the  so-called  ''brassy  corpuscles"  occur,  and 
only  in  such  infections.  At  every  stage  of  development  of  the  plasmodia  the 
infected  red  cell  is  smaller  than  normal,  and  is  generally  somewhat  irregular 
in  shape.  In  these  infections  only  the  "ring-forms"  and  the  young  pigmented 
bodies  are  found  in  the  peripheral  blood  in  the  vast  majority  of  cases.  The 
red  cell  is  never  entirely  fdled  by  either  of  these  plasmodia,  generally  not  more 
than  one-half  of  the  cell  being  occupied  when  the  parasites  are  fully  developed. 
The  occurrence  of  crescents  is  diagnostic  of  aestivo-autumnal  infections.  A 
diagnosis  of  aestivo-autumnal  infection  may  be  made  when  repeated  examina- 
tions of  the  blood  never  show  any  but  hyaline  "ring-forms"  and  small  pigmented 
forms  to  be  present,  for  in  tertian  and  quartan  infections  the  larger  develop- 
mental forms  will  be  present  as  well  as  sporulating  bodies. 

The  terian  aestivo-autumnal  plasmodium  is  differentiated  from  the 
quotidian  by  its  larger  size,  the  occurrence  of  several  granules  of  lighter  brown 
pigment;  its  less  refractive  outline;  greater  amoeboid  motion;  and  by  the  fact 
that  the  tertian  crescents  are  more  slender,  both  male  and  female,  than  are  the 
quotidian,  and  contain  a  greater  amount  of  pigment.     They  are  also  smaller. 

For  a  more  extended  discussion  of  the  differential  features  of  the  malarial 
plasmodia  the  reader  is  referred  to  the  chapter  treating  of  the  morphology  of 
the  plasmodia  (Chapter  II). 

Demonstration  of  Plasmodia  in  Sections  of  Tissue. — It  is  often  desir- 
able to  demonstrate  the  plasmodia  in  the  organs  of  fatal  cases  of  malaria,  and 
this  may  be  done  by  taking  smears  of  the  organic  pulp,  and  staining  as  with 
blood  smears,  or  by  sectioning  the  invaded  organs  and  then  staining.  In 
most  instances,  where  it  is  desired  to  simply  prove  or  disprove  the  existence 
of  a  malarial  infection,  all  that  is  necessary  is  to  make  a  few  smears  of  the  splenic 
pulp  by  simply  drawing  the  microscopic  slide  across  the  cut  surface  of  the 
organ  and  then  staining  with  Wright's  stain.  Where  it  is  desired,  however,  to 
demonstrate  the  exact  situation  of  the  plasmodia  in  the  tissues,  it  is  necessary 
to  section  the  invaded  organs,  and  to  stain  the  section  with  some  suitable 
solution.     The  following  method  I  have  found  satisfactory: 

The  tissue  is  cut  into  small  blocks  not  over  3  mm.  in  diameter,  and  then 
passed  through  50,  65,  75,  and  90  per  cent,  alcohol,  and  finally  absolute  alcohol, 
allowing  about  three  hours  in  each  alcohol.  The  tissue  should  then  be  washed 
and  left  for  two  hours  in  chloroform,  after  which  it  is  embedded  in  paraffin  at 
a  temperature  which  will  just  keep  the  paraffin  in  a  fluid  state.  The  tissue 
should  remain  in  the  paraffin  bath  for  about  six  hours,  and  then  the  paraffin 
allowed  to  harden  around  it,  after  which  sections  may  be  cut  with  any  good 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       7>21 

microtome,  the  sections  to  be  as  thin  as  possible,  as  only  in  very  thin  sections 
will  the  plasmodia  show  to  advantage  when  stained. 

For  staining  Delafield's  haematoxylin  is  very  useful,  as  is  methylene 
blue  and  Giemsa's  stain.  It  is  difficult  to  secure  good  results  with  any  of 
the  modifications  of  the  Romanowsky  method,  although  I  have  seen  fairly 
good  staining  with  the  Wright  stain. 

The  technic  of  staining  the  sections  is  as  follows: 

The  section  is  removed  from  the  microtome  and  placed  upon  a  slide  which 
has  smeared  upon  its  surface  a  little  egg-albumin  water.  The  section  is  then 
successively  washed  in  xylol  to  remove  the  paraffin  in  95  per  cent,  and 
absolute  alcohol  and  water;  and  stained  with  haematoxylin  and  eosin,  thionin, 
or  Wright's  stain.  The  stain  should  be  allowed  to  remain  for  from  ten  minutes 
to  an  hour,  then  washed  off  with  alcohol,  and  the  sections  cleared  in  oil  of  clove. 
They  are  then  mounted  in  balsam,  and  are  ready  for  examination.  Care  should 
be  taken  in  dehydrating  with  alcohol  that  all  the  water  is  removed,  and  if  it  is 
found  that  in  order  to  do  this  too  much  stain  is  removed,  the  alcohol  should  be 
blotted  off  and  the  section  covered  with  oil  of  clove,  which  will  complete  the 
dehydration  without  removing  so  much  of  the  stain.  Care  should  be  taken 
that  during  no  stage  of  the  staining  the  sections  become  dry.  In  sections  of 
tissue  properly  stained  the  plasmodia  show  well,  but  appear  much  smaller  than 
in  stained  smears  or  in  fresh  blood  specimens,  owing  to  the  shrinkage  brought 
about  by  the  hardening  and  embedding  processes.  In  sections  the  chromatin 
staining  is  very  seldom  well  defined,  and  the  infected  corpuscles  do  not  show 
distinctly,  the  plasmodia  appearing  to  lie  free  within  the  capillaries.  The 
parasites  are  most  numerous  in  the  smaller  capillaries  and  are  scarce  in  the 
large  vessels.  In  the  smaller  vessels  the  plasmodia  occur  chiefly  along  the  walls 
of  the  vessel,  very  few  being  observed  toward  the  center,  but  in  the  minute 
capillaries  the  plasmodia  occur  in  masses  which  often  occlude  them.  The 
plasmodia  are  often  at  different  stages  of  development  or  they  may  be  prac- 
tically all  in  one  stage  of  their  life  cycle.  In  aestivo-autumnal  infections  it  is 
common  to  find  the  capillaries  of  the  brain  and  of  the  spleen  filled  with  spherical 
pigmented  plasmodia  of  the  same  size  and  appearance.  In  all  cases  of  perni- 
cious malaria  or  cases  suspected  to  be  such  smears  of  the  brain  and  of  the 
spleen,  as  well  as  of  the  bone-marrow,  should  be  stained  and  examined,  and  in 
addition  sections  of  the  brain  and  spleen  should  be  made. 

The  Diagnostic  Value  of  Free  Pigment  and  Pigmented  Leucocytes. — 
The  presence  of  free  pigment  in  the  blood  is  characteristic  of  malarial  infection, 
but,  unfortunately,  is  of  little  diagnostic  value,  as  such  pigment  is  so  easily 
simulated  by  particles  of  dirt,  artefacts,  and  other  matter  that  it  is  generally 
impossible  to  be  sure  of  the  diagnosis  of  malarial  pigment.  It  is,  therefore, 
unjustifiable  to  make  a  diagnosis  of  malaria,  because  material  resembling 
malarial  pigment  is  observed  free  in  the  blood  plasma.  Wlien,  however,  the 
pigment  is  observed  enclosed  in  mono-  or  polynuclear  leucocytes;  when  it  is  of 
a  characteristic  golden-brown  or  blackish  color;  and  when  several  pigmented 


6~- 


DIAGXOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 


leucocytes  are  observed  in  two  or  more  smears,  carefully  prepared,  we  are 
justified  in  making  a  diagnosis  of  malarial  infection,  either  past  or  present ;  but 
under  such  circumstances  it  is  impossible  to  diagnose  the  variety  of  malarial 
infection  present.  The  pigment  is  generally  observed  in  the  large  mono- 
nuclear leucocytes,  but  in  my  experience  it  has  not  been  rare  to  observe  pigment 
in  the  polynuclear  leucocytes.  To  one  who  has  had  experience  in  the  examina- 
tion of  malarial  blood  the  pigmented  leucocyte  is  easy  of  recognition  and  is 
always  indicative  of  a  malarial  infection. 

The  Diagnostic  Significance  of  Blood  Counts. — I  have  already  men- 
tioned the  increase  of  large  mononuclears  in  chronic  malarial  infections  and  in 
infections  in  which  several  relapses  have  occurred.  This  mononuclear  in- 
crease is  believed  by  Rodgers  to  be  of  diagnostic  importance,  but  I  am  unable 
to  agree  with  him  that  such  an  increase  is  diagnostic  of  malarial  infection.  A 
similar  increase  is  observed  in  other  acute  fevers  as  well  as  in  chronic  infections. 
Thus  in  dengue  one  of  the  most  characteristic  blood  pictures  is  a  mononuclear 
increase,  while  in  kala-azar  the  same  condition  occurs.  I  consider  it  very  unsafe 
to  base  a  diagnosis  of  malaria  upon  the  differential  blood  count,  and  I  believe 
that  further  research  will  show  that  a  mononuclear  increase  is  observed  in  most 
infections  due  to  the  Protozoa. 

Agglutination  Test  in  Diagnosis. — It  has  been  demonstrated  by  La 
Monaco  and  Panichi  that  the  blood  serum  of  patients  suffering  from  malarial 
fever  possesses  agglutinative  power  over  the  blood  of  healthy  individuals, 
while  Stephens  and  Christophers  have  noted  the  agglutination  of  malarial 
sporozoites  by  malarial  blood.  This  subject  is  of  great  scientific  interest,  as  it 
would  indicate  the  presence  of  specific  precipitins  or  agglutinins  in  malarial 
blood,  but  the  agglutination  test  is  of  no  practical  value  at  present  in  the  diagno- 
sis of  malarial  infection. 

The  laboratory  diagnosis  of  malarial  infection  rests  upon  the  finding  of 
the  plasmodia  or  of  pigmented  leucocytes  in  either  fresh  or  stained  specimens 
of  blood  or  in  smears  or  sections  of  tissue  from  a  suspected  case.  The  best 
time  for  the  examination  of  the  blood  in  tertian  and  quartan  cases  is  a  few  hours 
before  the  chill  or  at  the  time  of  the  chill,  while  in  aestivo-autumnal  infections 
the  best  time  for  blood  examination  is  a  few  hours  before  the  expected  paroxysm. 
In  the  latter  class  of  cases  it  is  not  unusual  to  find  that  the  time  of  onset  of  the 
paroxysm  cannot  be  foretold,  and  in  such  instances  the  blood  should  be  re- 
peatedly examined,  at  hourly  intervals,  until  several  smears  have  been  looked 
over,  and  thus  a  negative  result  assured,  as  not  infrequently  the  plasmodia  are 
very  few  in  number  in  the  peripheral  blood  and  only  by  repeated  examinations 
will  their  presence  be  demonstrated. 

Puncture  of  Spleen. — I  have  never  found  puncture  of  the  spleen  necessary 
from  a  diagnostic  standpoint,  and  I  would  earnestly  advise  against  this  pro- 
cedure for  such  a  purpose.  The  operation  is  always  dangerous  where  the  spleen 
is  enlarged  and  softened,  and  it  should  only  be  undertaken  by  one  skilled  in  the 
technic  and  under  the  most  careful  precautions  as  regards  asepsis  and  guard- 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       323 

ing  against  haemorrhage.  The  spleen  should  never  be  punctured  unless  it 
reaches  well  below  the  border  of  the  ribs,  as  otherwise  there  is  great  danger 
that  the  capsule  will  be  torn  by  the  needle  coming  in  contact  with  the  ribs 
during  inspiration,  for  it  is  almost  impossible  to  guard  against  more  or  less 
movement  of  the  organ  during  the  pain  of  the  puncture. 

The  Examination  of  the  Malarial  Mosquitoes. 

It  is  essential  to  the  student  of  malaria  that  he  be  able  to  recognize  the 
malarial  mosquitoes,  and  that  he  possess  enough  knowledge  of  their  habits  to  be 
able  to  rear  them  and  thus  be  enabled  to  procure  specimens  for  experimental 
purposes.  In  this  section  I  shall  give  briefly  the  most  important  diagnostic 
features  which  serve  to  distinguish  the  Anophelinae  from  other  mosquitoes, 
features  which  are  easily  learned  and  a  knowledge  of  which  will  enable  any  one, 
who  cares  to  take  the  time,  to  recognize  the  presence  of  malarial  mosquitoes; 
general  directions  will  also  be  given  concerning  the  rearing  of  these  insects 
and  the  methods  of  using  them  in  experimental  work. 


Fig.  24. — Diagram  of  Typical  Anophelina. 

A,  Proboscis;  B,  palpi;  C,  Cylpeus;  D,  eye;  E,  occiput;  F,  prothoracic  lobe;  G,  mesothorax; 
H,  scutellum;  I,  metathorax;  J,  abdominal  segments;  K,  halter;  L,  legs;  M,  wing;  N,  antenna. 
(Modified  from  Theobald.) 

Diagnosis  of  Malarial  Mosquitoes. — The  Anophelinae,  or  malarial 
mosquitoes,  are  easily  differentiated  from  other  mosquitoes  by  certain  well 
marked  characteristics  of  the  adult  insect,  which  may  be  summarized  as  follows: 

1.  The  Relative  Length  of  the  Palpi  and  the  Proboscis. — In  the 
Anophelinae  the  palpi  of  the  female  are  as  long  as  the  proboscis,  while  in 
the  female  Culicinae  the  palpi  are  short,  stubby  structures.  An  examination 
of  the  palpi  and  proboscis  of  any  mosquito  will,  therefore,  enable  one  to  say 


324       DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 

whether  it  belongs  to  the  Anophelinae  or  the  Culicinae.  In  the  males  of  both 
the  Anophelinae  and  the  Culicinae  the  palpi  are  long  and  plumose,  being 
covered  with  delicate  hairs,  giving  a  plume-like  appearance. 

2.  The  Angle  of  the  Proboscis  with  the  Body. — In  the  Anophelinae 
the  proboscis  does  not  form  an  angle  with  the  rest  of  the  body,  but  continues  in 
a  direct  line  with  it,  thus  differing  from  Culex,  Stcgomyia,  and  Taenio- 
rhynchus,  in  which  the  proboscis  forms  a  distinct  angle  with  the  rest  of  the  body. 
This  characteristic  gives  mosquitoes  belonging  to  the  Anophelinae  a  peculiar 
"business-like"  appearance,  the  entire  insect  resembling  a  boring  instrument. 

3.  The  Attitude  when  Resting  Upon  a  Surface. — Mosquitoes  belong- 
ing to  the  Anophelinae,  when  resting  upon  a  flat  surface,  such  as  a  wall,  form  a 
distinct  angle  with  the  surface,  the  insect  resting  upon  the  first  two  pairs  of  legs, 
the  last  pair  floating  in  the  air  or  held  out  straight  behind  it.  In  many  instances 
the  angle  maintained  by  the  insect  is  almost  a  right  angle,  and  the  body 
is  always  on  a  line  with  the  probosis.  The  position  assumed  by  other  mos- 
quitoes, as  Culex,  is  well  described  as  "hunch-backed,"  the  tail  approaching 
the  resting  surface,  while  the  thorax  is  distinctly  higher  than  any  other  portion  of 
the  body,  thus  giving  the  "hunched"  appearance.  Certain  mosquitoes  rest 
with  the  body  parallel  to  the  resting  surface,  but  the  Anophelinae  alone  form  a 
distanct  angle  with  it.  One  species  belonging  to  the  Anophelinae,  Myzomyia 
culicifacies  Giles,  rests  with  its  body  parallel  to  the  resting  surface,  thus  resem- 
bling a  Culex,  but  this  is  the  only  exception  so  far  discovered  to  the  general  rule 
noted  (see  Fig.  20). 

4.  Most  of  the  Anophelinae  have  Spotted  Wings,  but  this  is  also  true 
of  at  least  a  few  other  mosquitoes.  However,  for  practical  purposes,  mosqui- 
toes having  distinctly  spotted  wings  may  be  classed  as  Anophelinae.  For 
species  determination  the  reader  is  referred  to  the  generic  table  given,  and  to 
Theobald's  classic  work  upon  these  insects. 

The  ova  of  the  Anophelinae  may  be  distinguished  by  the  fact  that  they  lie 
separately  upon  the  water,  or,  at  most,  are  only  connected  by  the  ends,  while 
the  ova  of  Culex  occur  in  boat-shaped  masses.  The  ova  of  the  Anophelinae  are 
also  provided  with  lateral  air-cells  or  "floats,"  which  are  characteristic.  The 
larvae  of  all  Anophelines  are  easily  distinguished  from  those  of  Culex  by  the 
absence  of  a  respiratory  siphon,  so  that  when  they  are  at  the  surface  of  the 
water  they  are  obliged  to  lie  nearly  parallel  to  it,  while  Culex  hangs  head  down- 
ward at  an  acute  angle  with  the  surface  of  the  water.  The  larvae  of  the  Anophe- 
linae have  smaller  heads  in  proportion  to  the  body  than  other  mosquito  larvae, 
and  they  move  in  a  much  more  jerky  manner  when  rising  to  the  surface  of  the 
water  (see  Fig.   18). 

The  Collection  of  Ova,  Larvae,  and  Adult  Mosquitoes. — The  ova  of  the 
Anophelinae  may  be  collected  along  the  edges  of  small  natural  pools,  but  they 
are  detected  with  difficulty,  and  a  much  more  satisfactory  method  of  obtaining 
them  is  to  catch  a  number  of  the  mature  insects,  confine  them  in  jars  containing 
water,  and  collect  the  ova  from  the  surface  of  the  water  for  examination. 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       325 

The  larvae  of  the  Anophelinae  may  be  collected  from  the  edges  of  small 
puddles,  shallow  pools,  and  slowly  running  streams,  by  muddying  the  water, 
when  the  larvae,  if  present,  may  be  clearly  distinguished  by  reason  of  their 
grayish  color,  and  can  be  easily  removed  by  aid  of  a  small  dipper.  The  adult 
insects  may  be  captured  at  night  by  placing  a  lamp  so  that  a  portion  of  a  wall  is 
but  slightly  lighted,  upon  which  the  mosquitoes  will  gather,  and  from  which  they 
may  be  captured  by  aid  of  a  test-tube  having  a  large  mouth,  or  of  small  straight 
glass  cylinders,  closed  at  one  end.  Cotton  should  be  used  to  close  the  open  end 
of  the  cylinder  or  tube.  If  it  is  desired  to  kill  the  mosquitoes  as  they  are  col- 
lected, a  cyanide  bottle  may  be  used,  or  a  little  cotton  saturated  with  chloro- 
form may  be  placed  at  the  bottom  of  the  test  tube  or  cylinder.  When  it  is 
desired  to  collect  mosquitoes  for  rearing  or  for  experimental  work  the  test-tube 
or  cylinder  should  be  gently  placed  over  the  insect,  as  it  rests  upon  the  wall,  and 
then  gently  moved  across  the  surface  of  the  wall,  when  the  insect  will  fly  to  the 
closed  end,  and  the  tube  may  then  be  sealed  with  the  cotton  stopper.  The  best 
places  to  search  for  the  adult  Anopheles  is  in  the  dark  corners  of  rooms;  under 
surfaces  of  tables  and  sinks;  in  closets;  and  about  the  base-boards  of  rooms  not 
exposed  to  sunlight.  In  regions  in  which  these  insects  are  common  a  search  of 
such  localities  will  always  result  in  finding  many  specimens. 

To  Kill  and  Mount  Mosquitoes. — Mosquitoes  may  be  killed  by  exposing 
them  to  tobacco  smoke,  the  fumes  of  chloroform,  or  by  using  a  cyanide  bottle 
in  their  capture.  If  chloroform  is  used  be  careful  not  to  wet  the  insect,  as 
by  so  doing  the  scales  are  removed  from  the  wings  and  thus  a  distinguishing 
feature,  useful  in  the  differentiation  of  species,  is  lost.  In  order  to  properly 
mount  mosquitoes  for  purposes  of  preservation  the  following  apparatus  is  nec- 
essary: Cardboard,  preferably  white;  entomological  pins  and  forceps,  the 
pins  being  large  and  small  (No  20) ;  and  glass  specimen  tubes  and  corks. 

A  disk,  slightly  smaller  than  the  diameter  of  the  specimen  tube,  is  cut  from 
the  cardboard,  and  a  fine  entomological  pin  is  pushed  through  the  center  of 
the  disk  for  about  two-thirds  its  length.  The  mosquito  is  placed  upon  its 
back  upon  a  piece  of  white  paper,  and  transfixed  with  the  fine  entomological 
pin  which  has  attached  to  it  the  paper  disk,  the  pin  entering  the  insect  at  the 
center  of  the  under  surface  of  the  thorax,  and  emerging  as  close  to  the  center  of 
the  dorsum  of  the  thorax  as  possible,  where  it  should  extend  for  about  a  milli- 
meter. The  entire  specimen  is  now  mounted  by  transfixing  the  edge  of  the 
paper  disk  with  a  coarse  entomological  pin  or  a  common  pin  in  a  direction 
opposite  that  of  the  fine  pin,  for  three-quarters  of  its  length,  the  point  being 
pushed  into  the  cork  of  the  specimen  tube  upon  its  inner  side  (see  Fig.  25). 

To  Dissect  Mosquitoes. — In  order  to  make  good  dissections  of  the  Anophe- 
linae for  the  purpose  of  detecting  malarial  infection  or  for  studying  the  develop- 
ment of  the  plasmodia  within  these  insects  the  following  apparatus  is  necessary: 
Microscopic  slides  and  cover-glasses;  fine  dissecting  needles,  mounted  in  handles; 
a  good  dissecting  microscope,  and  some  normal  salt  solution.  A  compound 
microscope  with  high-power  lenses  is,  of  course,   necessary  for  studying  the 


26       DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 


development  of  the  plasmodia.  The  portions  of  the  mosquito  of  greatest 
interest  to  the  student  of  malaria  are  the  salivary  glands  and  the  mid-gut  or 
stomach. 

To  Dissect  the  Salivary  Glaxps. — While  in  most  works  upon  mosquitoes 
it  is  said  to  be  a  simple  procedure  to  dissect  out  the  salivary  glands,  it  will  be 
found  in  practice  that  it  is  indeed  a  very  difficult  task  to  secure  perfect  specimens 
of  these  glands,  although  it  is  comparatively  easy  to  secure  portions  of  the  glands 
sufficiently  perfect  to  allow  of  demonstrating  the  sporozoites.  The  glands  are 
situated  within  the  thorax,  lying  ventrally,  commencing  at 
the  posterior  portion  of  the  neck  and  ending  at  the  level  of 
the  first  pair  of  legs.  The  simplest  way  of  securing  them 
for  study  is  to  cover  the  insect  with  salt  solution  and  place 
it  so  that  the  head  is  toward  the  dissecting  hand.  While 
the  needle  of  the  left  hand  steadies  the  thorax,  the  needle 
of  the  right  hand  makes  traction  upon  the  head,  separating 
it  gently  from  the  body.  If  the  operation  has  been  suc- 
cessful it  will  be  observed  that  a  little  white  bit  of  tissue 
has  been  extracted  from  the  thorax  with  the  head,  and 
upon  examination  with  the  microscope  it  will  be  observed 
that  in  this  bit  of  tissue  lie  the  salivary  glands,  which 
may  now  be  separated  from  the  head  and  carefully 
studied.  The  glands  may  also  be  isolated  by  making  an 
antero-posterior  cut  in  the  ventral  portion  of  the  thorax 
and  a  connecting  cut  at  right  angles  with  it,  and  then  sep- 
arating the  glands  from  the  portion  of  thorax  removed  by 
teasing  gently  in  salt  solution,  but  this  method  almost 
always  results  in  mutilation  of  the  glands. 

In  order  to  determine  the  presence  of  malarial  sporo- 
zoites the  glands  are  pressed,  upon  firmly  enough  to 
rupture  them,  when  the  sporozoites,  if  present,  will  be 
liberated  in  the  salt  solution.  A  one-sixth  lens  should  be 
used  for  the  examination  and  as  little  light  as  possible. 
The  sporozoites  appear  as  fine,  hyaline,  curved  rods,  having  more  or  less  active 
motion  in  some  instances,  lying  free  in  the  salt  solution  or  in  large  numbers 
within  the  cells  of  the  salivary  glands.  They  measure  about  14^  in  length, 
and  about  2^  in  width.  They  may  be  permanently  preserved  by  making  thin 
films  of  the  salt  solution  containing  them  upon  glass  slides,  and  drying  and 
staining  with  Wright's  stain,  as  described  for  blood  films.  For  the  study  of 
the  morphological  structure  of  the  sporozoites  a  one-twelfth  lens  is  essential. 
In  stained  specimens  the  sporozoites  are  fusiform  in  shape,  consisting  of  blue 
stained  protoplasm  having  a  mass  of  red  chromatin  at  the  center  or  distributed 
along  it  in  the  form  of  a  narrow  ribbon  or  thread. 

To  Dissect  the  Mid-intestine  or  Stomach. — The  dissection  of  the 
mid-intestine  of  the  mosquito  is  essential  if  we  are  to  study  the  development 


Fig.  25. — Method  of 
Mounting  and  Pre- 
serving Mosquitoes. 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.   •    327 

of  the  malarial  plasmodia  within  this  insect,  and  with  a  little  practice  it  is  easily 
accomplished.  The  insect,  from  which  the  wings  and  legs  have  been  removed 
by  dissecting  forceps,  is  moistened  with  a  little  alcohol  and  then  immersed  in 
the  salt  solution  upon  a  glass  slide,  a  dark  background  being  employed  to 
facilitate  the  dissection.  Placing  the  insect  upon  its  back,  the  left-hand  needle 
is  used  to  steady  it,  while  with  the  right  a  nick  is  made  in  the  chitin  on 
either  side  as  near  the  posterior  end  as  is  possible;  the  left-hand  needle  is  now 
placed  firmly  upon  the  thorax,  and  the  right  upon  the  end  of  the  abdomen 
and  gentle  traction  exerted,  when  between  the  separating  abdominal  segments 
a  white  mass  of  viscera  will  be  observed;  the  traction  is  continued  until  it 
is  possible  to  separate  easily  the  anterior  end  of  the  mid-gut,  which  consists  of 
an  anterior  tubular  portion  and  a  posterior  saccular  portion,  lying  at  the  level  of 
the  fifth  and  sixth  abdominal  segments,  and  which  is  the  portion  in  which 
zygotes  will  be  found  if  the  mosquito  is  infected.  If  it  is  found  that  this  portion 
of  the  mid-gut  contains  blood,  the  specimen  should  be  discarded,  unless  it  be 
desired  to  study  exflagellation,  as  the  zygotes  cannot  be  distinguished  easily 
in  the  mid-gut  when  undigested  blood  is  present.  In  examining  mosquitoes 
for  malarial  infection  it  should  be  remembered  that  only  a  comparatively 
few  of  the  insects  collected  will  prove  to  be  infected  and  therefore  several  insects 
should  be  examined  before  a  negative  report  is  of  value. 

Demonstration  of  Zygotes. — The  specimen  of  the  mid-gut  or  stomach 
should  be  examined  with  both  a  one-sixth  and  a  one-twelfth  lens,  the  larger 
zygotes  being  easily  visible  with  a  one-sixth  lens,  while  for  the  detection  of  the 
earlier  stages  a  one-twelfth  lens  is  necessary.  Any  granule  resembling  malarial 
pigment  should  be  carefully  inspected,  as  by  so  doing  the  zygotes  are  most 
quickly  discovered,  even  in  the  earliest  stage  of  development.  The  earliest 
stage  is  an  oval  or  spherical  body,  about  8//  in  diameter,  containing  pigment,. 
the  character  of  which  varies  with  the  species  of  the  plasmodium,  the  aestivo- 
autumnal  zygotes  having  black  pigment  collected  in  a  clump;  the  tertian,  yellow- 
ish or  brown  pigment  collected  in  delicate  strands;  and  the  quartan,  coarse 
dark  brown  pigment  collected  in  a  large  clump.  As  development  advances,  the 
species  of  the  zygote  becomes  indistinguishable,  and  each  organism  is  surrounded 
by  a  well-developed  cyst  wall,  within  which  the  sporoblasts  are  developed.  At 
a  later  period  of  development  the  sporozoites  may  be  observed  packing  the 
cysts,  which  have  become  so  large  as  to  be  visible  with  a  two-thirds  inch  lens, 
while  the  sporozoites  are  easily  seen  with  a  one-sixth  lens.  The  pigment  disap- 
pears in  many  of  the  zygotes  as  development  proceeds,  but  many  contain  black 
clumps  of  material,  which  probably  represents  residual  pigment,  or  parasitic 
infection. 

To  Section  Mosquitoes. — The  following  method,  advocated  by  Stephens 
and  Christophers  and  given  in  their  own  words,  is  an  excellent  one  when  it 
is  desired  to  section  infected  mosquitoes  for  purposes  of  study  and  demon- 
stration. 

1.  Select  Anophelines  free  from  blood  and  kill  by  chloroform  vapor. 


o 


28       DIAGNOSIS,   PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 


2.  Fix  in  (a)  acetic  alcohol  for  5  or  10  minutes  (glacial  acetic  acid  one 
part,  absolute  alcohol,  six  parts,  chloroform,  three  parts);  wash  in  absolute 
alcohol  till  free  from  acid  (it  is  often  advisable,  especially  with  thick  flies,  to 
nick  the  chitin  at  some  unessential  part  in  order  to  allow  penetration  of  the 
fixative),  or  (b)  sublimate  alcohol,  or  (c)  absolute  alcohol,  15  minutes. 

3.  Place  in  1  per  cent,  celloidin  for  a  day  and  in  3  per  cent,  celloidin  for 
another  clay.  These  times  may  with  advantage  be  increased,  but  sometimes 
a  few  hours  only  suffice.  (The  solution  of  celloidin  is  made  by  dissolving  dry 
chips  in  50  per  cent,  alcohol  and  then  in  a  day  or  so  adding  50  c.c.  of  ether. 

4.  Transfer  to  cedar- wood  oil,  and  when  the  mosquito  sinks  transfer  to 

5.  Paraffin  for  half  to  one  hour,  and  then  section  and  strain. 

To  Rear  Mosquitoes. — Many  species  of  Anopheles  are  reared  with  great 
difficulty  under  artificial  conditions,  but  others  breed  well  in  confinement.  The 
more  nearly  we  imitate  nature  in  the  surroundings  of  our  rearing  cages  for 
mosquitoes,  the  greater  will  be  our  success  in  rearing  these  insects.  Cages 
built  of  light  wood  and  covered  with  fine  wire  gauze  are  suitable  and  each 
should  contain  a  vessel  of  water.  Glass  jars  containing  water  and  vegetable 
material  make  good  breeding-places  ,  and  pieces  of  large  bambo  "sawed  off  some 
distance  from  the  joints  have  been  used  with  great  success  by  many  investi- 
gators. When  jars  or  other  open-mouthed  receptacles  are  used  the  open  end 
should  be  covered  with  gauze. 

A  goodly  number  of  mosquitoes  should  be  captured,  both  males  and 
females,  and  liberated  in  the  breeding  receptacle,  which  should  be  placed  in  a 
shaded  part  of  the  room  or  in  a  closet.  The  males  soon  die,  but  the  females 
will,  many  of  them,  lay  their  eggs,  and  in  due  time  the  larvae  will  appear.  The 
insects  may  be  fed  by  placing  small  pieces  of  banana  within  the  cages  or  by 
laying  slices  of  banana  upon  the  gauze  covering  the  jar  or  other  breeding  place. 
Dead  insects  should  be  removed  each  morning,  and,  with  care,  adult  insects  may 
be  kept  for  many  days  in  this  manner.  If  it  is  desired  to  breed  out  the  larvae 
they  should  be  removed  from  the  cage  and  placed  in  a  jar  of  water  exposed  to 
light  but  not  to  excessive  heat.  The  insects  live  longer  in  glass  jars  than  in 
gauze  cages,  as  a  general  rule. 

Feeding  Experiments. — When  mosquitoes  are  required  for  feeding 
experiments  they  should  be  removed  from  the  breeding  jar  and  transferred  to  a 
glass  jar  having  a  wide  neck  covered  with  cotton  gauze,  where  they  should  be 
kept  for  at  least  three  days  without  food.  It  is  better  to  use  mosquitoes  bred  out 
from  the  larvae  in  such  experiments,  as  they  are  sure  to  be  free  from  infection, 
and  will  bite  readily  48  hours  after  birth.  At  least  25  mosquitoes  should  be 
used  in  each  feedng  experiment,  in  two  jars.  A  patient  is  selected  whose 
blood  contains  gametes,  and,  after  dark,  allowed  to  place  his  arm  over  the 
gauze  covered  neck  of  the  jars.  Biting  is  hastened  by  washing  the  arm  in  warm 
water  just  before  the  experiment.  The  insects  usually  bite  within  half  an 
hour,  but  it  will  be  found  that  some  of  them  require  a  longer  time  to  bite  and 
that  some  will  not  bite.     It  is  well  to  wait  for  an  hour  before  ceasing  the  ex- 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       329 

periment,  thus  allowing  the  insects  plenty  of  time.  The  jar  should  be  labeled 
with  the  time  and  date  of  biting,  and  the  insects  dissected  at  various  intervals 
after  the  first  twenty-four  hours  if  it  is  desired  to  follow  the  development  of 
the  plasmodia,  or  kept  for  twelve  days  before  allowing  them  to  bite  if  we 
desire  to  transmit  malaria  experimentally. 

The  Diagnosis  of  Malarial  Regions. — Before  establishing  residences  or 
permanent  military  camps  or  posts  in  the  tropics  or  in  regions  in  which  mos- 
quitoes capable  of  transmitting  malaria  abound,  it  is  of  the  greatest  importance 
that  the  presence  or  absence  of  the  malarial  fevers  be  determined  and  in  the  ex- 
amination of  the  blood  of  the  natives,  and  the  mosquitoes,  as  to  the  presence  of 
malarial  infection,  we  possess  methods  which  enable  us  to  make  a  malarial 
survey  of  any  locality. 

A  map  of  the  locality  should  be  obtained  and  there  should  be  marked  upon 
it  the  location  of  the  breeding-places  of  mosquitoes  and  the  species  found  in  each 
breedery,  also  whether  any  of  the  insects  examined  were  found  to  be  infected 
with  plasmodia;  the  dwellings  of  any  individuals  found  infected  with  malaria 
during  the  blood  examination  of  the  natives  should  be  indicated  upon  the  map, 
and  thus  the  relation  of  the  breeding-places  of  the  mosquitoes  to  such  infections 
will  be  clearly  shown.  The  map  should  also  show  the  ratio  of  infected  indivi- 
duals and  of  infected  mosquitoes,  and  the  most  dangerously  infected  localities. 
The  work  of  a  few  days  in  the  examination  of  the  blood  of  the  natives,  the 
dissection  of  mosquitoes,  and  the  search  for  the  breeding-places  of  these  insects 
will  result  in  a  most  valuable  mass  of  data  enabling  one  to  judge  of  the  advisa- 
bility of  locating  in  the  region  examined.  Such  a  preliminary  survey  of  the 
malarial  endemicity  of  localities  is  of  the  very  greatest  sanitary  importance  in 
the  selection  of  camp  sites  of  a  permanent  nature  or  sites  for  permanent  military 
posts  in  the  tropics  and  in  the  malarial  regions  of  the  temperate  zones. 


CHAPTER  II. 

The  Clinical  Diagnosis  of  the  Malarial  Fevers;  The  Differential 
Diagnosis  of   the   Malarial  Fevers. 

As  I  have  stated  the  diagnosis  of  malarial  infection,  without  the  aid  of 
laboratory  assistance,  is  often  impossible,  and  still  more  frequently  is  it  impos- 
sible to  diagnose  the  variety  of  infection  present.  In  uncomplicated  and  single 
tertian  and  quartan  infections  a  diagnosis  may  be  reached  by  the  study  of  the 
temperature  chart,  the  regularly  recurring  paroxysms  of  fever  being  sufficient  to 
establish  the  type  of  infection  present,  but  in  many  cases  of  both  tertian  and 
quartan  malaria  the  temperature  chart  is  misleading,  the  paroxysms  occurring 
at  irregular  intervals,  thus  causing  an  irregular  temperature  curve.  It  is  in  the 
aestivo-autumnal  infections,  however,  that  we  most  frequently  find  it  impos- 
sible to  arrive  at  a  diagnosis  without  the  aid  of  the  microscope,  for  these  in- 
fections occur  in  so  many  atypical  forms  that  the  diagnosis  from  clinical 
symptoms  alone  is  seldom  easy  and  very  frequently  impossible.  The  micro- 
scopical examination  of  the  blood  is  the  only  infallible  method  of  arriving  at  a 
diagnosis  and  should  never  be  neglected.  The  therapeutic  test  by  quinine,  i.e., 
the  administration  of  the  drug  in  suspected  cases,  has  been  lauded  as  a  means  of 
diagnosis,  but  the  malarial  fevers  are  not  the  only  fevers  that  are  influenced  by 
this  drug,  and  it  is  illogical  to  regard  every  fever  that  declines  after  the  ad- 
ministration of  quinine  as  malarial.  Added  to  the  worthlessness  of  the 
quinine  test  as  a  diagnostic  test  of  malaria,  it  is  dangerous  to  rely  upon  this 
drug  in  diagnosis,  for  it  is  usually  given  by  the  mouth  in  such  instances 
and  it  is  well  known  that  many  pernicious  infections  are  very  resistant  to 
quinine  when  so  administered.  In  this  way  the  diagnosis  may  be  delayed  until 
the  patient  is  in  grave  danger  or  even  moribund.  While  it  is  undoubtedly  true, 
as  stated  by  Osier,  that  any  fever  which  resists  the  action  of  quinine  properly 
administered  for  over  four  or  five  days  is  not  malarial  in  character,  it  is  foolish 
to  wait  so  long  to  establish  our  diagnosis  when  a  few  moments'  examination  of 
the  blood  will  enable  us  to  reach  the  same  conclusion. 

Certain  factors  are  of  value  in  arriving  at  a  suppositional  diagnosis  of 
malarial  fever,  among  the  most  important  of  which  may  be  mentioned  the  time 
of  occurrence  of  the  disease;  the  character  of  the  locality  in  which  the  patient 
is  resident  or  from  which  he  has  come;  the  location  of  the  dwelling-house  in 
relation  to  water  and  thus  to  possible  breeding-places  of  mosquitoes;  the  history 
of  previous  attacks;  the  periodicity  of  the  attacks;  the  species  of  mosquitoes 
present;  and  the  occurrence  of  similar  fevers  in  other  members  of  the  family. 

Diagnosis  of  the  Various  Forms  of  Malarial  Fever. — A  differential 

33° 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       33 1 

diagnosis  of  the  various  types  of  malarial  infection  is  most  quickly  and  scientifi- 
cally made  by  an  examination  of  the  blood.  In  this  way  the  entire  life  cycle 
of  the  tertian  and  quartan  plasmodium  may  be  studied,  and  the  aestivo- 
autumnal  plasmodia  easily  differentiated.  Where,  however,  an  examination 
of  the  blood  is  impracticable,  clinical  symptoms  have  to  be  relied  upon  to 
determine  the  type  of  infection  and  in  a  limited  proportion  of  cases  such 
symptoms  are  sufficient. 

Tertian  Infection. — The  temperature  range  in  uncomplicated  cases  of 
tertian  infection  is  so  typical  that  a  temperature  chart  is  often  all  that  is  needed 
to  enable  us  to  make  the  diagnosis.  The  occurrence  of  a  definite  paroxysm, 
accompanied  by  chill,  fever,  and  sweating,  every  48  hours,  is  generally  sufficient 
to  prove  the  type  of  malaria  present,  but  certain  cases  are  indistinguishable 
clinically  from  mild  tertian  aestivo-autumnal  infections,  while  if  double  tertian 
infections  be  present  or  small  doses  of  quinine  have  been  administered,  it 
becomes  impossible  to  distinguish  the  type  of  infection  present  without  the  aid 
of  the  microscope. 

Quartan  Infection.- — In  uncomplicated  cases  of  quartan  infection  the 
temperature  chart  is  absolutely  characteristic.  The  occurrence  of  a  paroxysm 
of  chill,  fever,  and  sweating  every  seventy-two  hours  is  absolutely  characteristic 
of  quartan  malarial  infection  and  we  may  safely  make  a  diagnosis  of  such 
infection  under  such  conditions,  but  double  and  triple  infections  occur  in  which 
the  temperature  chart  is  untrustworthy,  and  in  these  we  have  to  depend  upon  the 
microscope  in  diagnosing  the  type  of  malaria  present. 

Quotidian  Aestivo-atumnal  Infection. — When  an  aestivo-autumnal 
infection  is  known  to  be  present,  the  diagnosis  of  the  quotidian  form  from  the 
tertian  is  comparatively  easily  made,  because  of  the  usual  occurrence  of  a  distinct 
chill  in  the  quotidian  form  and  the  character  of  the  temperature  curve.  The 
differential  diagnosis  of  this  type  from  a  double  tertian  or  triple  quartan  infec- 
tion is,  however,  impossible  without  the  aid  of  the  microscope. 

Tertian  Aestivo-autumnal  Infection. — While  the  diagnosis  of  the 
tertian  type  of  aestivo-autumnal  fever  from  the  clinical  symptoms  alone  is  very 
often  impossible,  there  not  infrequently  occur  cases  in  which  this  form  of 
malarial  infection  may  be  diagnosed  from  the  temperature  chart  alone.  I  have 
already  described  the  peculiar  range  of  the  temperature  in  tertian  aestivo- 
autumnal  infection  when  uncomplicated,  and  a  chart  showing  this  peculiar 
curve,  which  is  not  found  in  any  other  fever,  is  absolutely  diagnostic,  provided 
the  temperature  be  taken  at  least  every  four  hours.  It  is  obviously  illogical, 
however,  to  wait  several  days  until  such  a  typical  chart  is  obtained,  when  an 
examination  of  the  blood  upon  the  very  first  day  will  clear  up  the  diagnosis. 
In  tertian  aestivo-autumnal  fever  the  chill  is,  as  a  rule,  either  absent  or  very 
slight,  and  the  general  symptoms  of  no  value  in  making  a  differential  diagnosis, 
aside  from  the  temperature. 

Pernicious  Infections. — These  infections,  usually  due  to  the  aestivo- 
autumnal   plasmodia,   are   easily  diagnosed  from   the   benign  fevers   by  the 


332       DIAGNOSIS,  PROPHYLAXIS.  AND  TREATMENT  OF  MALARIAL  FEVERS. 

character  and  severity  of  the  symptoms,  which  have  already  been  described. 
From  other  disease  processes  they  can  very  seldom  be  diagnosed  without  the 
aid  of  the  microscope,  and  it  is  safe  to  say  that  hundreds  of  lives  have  been 
sacrificed  to  malaria  which  could  have  been  saved  had  an  examination  of  the 
blood  been  made  in  the  endeavor  to  arrive  at  a  diagnosis.  In  all  cases  in  which 
a  suspicion  of  malaria  exists,  and  especially  in  those  cases  presenting  pernicious 
symptoms,  the  first  thought  of  the  diagnostician  should  be  the  microscopical 
examination  of  the  blood. 

I  have  noted  the  most  important  differential  features  of  the  various  types 
of  malaria,  but  I  would  impress  upon  the  reader  the  vital  importance  of  an 
examination  of  the  blood  in  the  diagnosis  of  malaria.  The  data  we  possess 
regarding  the  occurrence  of  malarial  fevers  in  various  localities,  and  the  type 
of  infection  present,  are  almost  worthless,  because  the  cases  have  been  diagnosed 
upon  clinical  symptoms,  the  examination  of  the  blood  being  neglected, 
and  the  obsolete  classification  of  the  malarial  fevers,  so  often  observed  in  the 
vital  statistics  of  the  public  services,  is  directly  due  to  the  constant  endeavor 
to  diagnose  malaria  by  clinical  symptoms  instead  of  by  the  examination  of 
the  blood.  The  absurdity,  for  instance,  of  a  classification  of  malarial  fevers 
based  upon  the  intermittency  or  remittency  of  the  temperature  curve  is  evident 
at  once  to  one  who  has  had  even  a  limited  experience  with  these  fevers,  and  such 
classifications  are  a  reproach  to  scientific  medicine.  Aside,  however,  from  this 
aspect  of  the  subject,  the  life  of  many  patients  depends  upon  the  quick  recogni- 
tion of  the  malarial  infection,  and  this  is  only  possible  through  the  microscopical 
examination  of  the  blood. 

The  Differential  Diagnosis  of  the  Malarial  Fevers. 

The  differential  diagnosis  of  the  malarial  fevers  from  other  diseases  is 
only  possible,  in  many  instances,  by  an  examination  of  the  blood,  and  this 
should  never  be  neglected  when  we  are  called  to  see  a  fever  in  malarial  localities 
or  in  an  individual  returning  from  such  a  locality.  The  difficulty  of  a  differential 
diagnosis  by  aid  of  clinical  symptoms  alone  is  especially  great  in  the  case  of 
the  aestivo-autumnal  infections  in  which  the  occurrence  of  atypical  symptoms 
are  common  and  in  which  pernicious  symptoms  occur  which  simulate  those 
present  in  other  specific  diseases.  The  following  diseases  not  infrequently  have 
to  be  differentiated'  from  malarial  fever,  and  most  of  them  are  sometimes  so 
closely  simulated  by  malaria  that  the  differential  diagnosis  has  to  be  made  by 
the  microscope. 

Typhoid  Fever. — Perhaps  no  other  disease  has  been  so  often  mistaken  for 
malaria  as  has  typhoid,  and  if  there  is  anything  in  the  history  of  medicine  which 
proves  the  futility  of  attempting  to  diagnose  the  malarial  fevers  by  clinical 
symptoms  alone,  it  is  the  experience  of  our  surgeons  in  the  war  with  Spain. 
When  one  has  seen,  as  the  writer  has,  hundreds  of  cases  of  severe  typhoid 
diagnosed   as  remittent   malaria   and   treated   accordingly,   one   is  inevitably 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       333 

forced  to  the  conclusion  that  the  diagnosis  of  the  malarial  fevers  by  means  of 
clinical  symptoms  alone  is,  to  say  the  least,  attended  with  great  difficulty,  and 
places  the  patient  in  peril  of  his  life  in  many  instances.  At  least  three-fourths 
of  the  fevers  occurring  in  our  Southern  camps  during  1898  and  diagnosed  as 
"remittent  malarial  fever"  were,  in  reality,  typhoid,  as  shown  by  the  examina- 
tion of  the  blood  and  the  Widal  test.  Clinically,  the  confusion  of  these  two 
diseases  has  much  to  justify  it.  It  is  probable  that  a  typical  tertian  or  quartan 
malaria  is  never  suspected  to  be  typhoid,  or  vice  versa,  but  in  the  more  irregular 
aestivo-autumnal  infections  this  mistake  has  often  been  made.  This  is  so 
because  many  cases  of  aestivo-autumnal  malaria  present  the  same  sympto- 
matology, at  least  in  part,  as  typhoid,  and  without  an  examination  of  the  blood 
it  is  impossible  to  arrive  at  a  diagnosis.  The  mistake,  however,  of  considering  a 
typhoid  infection  as  one  of  malaria  after  the  administration  of  quinine  for  over 
five  days  without  result  is,  it  appears  to  me,  inexcusable,  yet  I  have  observed 
scores  of  cases  of  typhoid  given  large  doses  of  quinine  for  weeks  under  the 
impression  that  they  were  suffering  from  malarial  infection,  and  in  supposedly 
malarial  regions  almost  every  typhoid  patient  is  drenched  with  quinine  simply 
because  of  the  neglect  of  the  blood  examination. 

The  differential  diagnosis  depends  upon  the  microscopical  examination  of 
the  blood,  the  Widal  test,  and  the  therapeutic  test  by  quinine.  If  the  plasmodia 
are  present  in  the  blood  and  the  Widal  test  is  negative,  the  diagnosis  is  at  once 
established;  if  the  Widal  be  positive  and  there  is  no  history  of  a  previous  at- 
tack of  typhoid,  we  are  dealing  with  a  combined  infection,  but  it  should  be 
remembered  that  such  infections  are  very  rare,  and  a  careful  inquiry  should  be 
made  concerning  the  previous  occurrence  of  a  continued  fever;  if  the  Widal  test 
be  positive  and  no  plasmodia  are  present,  after  repeated  examinations,  the  case 
is  one  of  typhoid;  while  if  neither  the  plasmodia  be  present  nor  a  positive  Widal 
can  be  secured  after  repeated  trials,  the  fever  must  be  due  to  some  other  in- 
fection. If  a  blood  examination  is  impossible  and  a  Widal  test  cannot  be  made, 
the  administration  of  quinine  for  three  or  four  days  will  clear  up  the  diagnosis, 
as  if  the  case  is  malarial  the  quinine  will  reduce  the  temperature  within  five 
days,  if  properly  administered.  During  the  defervescence  of  the  fever  in  typhoid 
the  temperature  may  become  intermittent,  the  curve  resembling  that  of  a 
double  tertian  or  quotidian  aestivo-autumnal  infection.  (Chart  No.  19.) 
Chills  may  also  occur  at  this  time,  during  the  onset,  or  at  any  time  during  the 
course  of  the  disease;  thus  further  increasing  the  resemblance  to  malaria,  and  in 
such  cases  a  diagnosis  is  often  made  of  "  typho-malarial"  fever.  Any  diagnosis 
of  malarial  fever  under  such  circumstances  is  utterly  worthless  unless  confirmed 
by  a  blood  examination.  With  the  Widal  test,  and  the  improved  methods  we 
.  possess  of  staining  the  malarial  plasmodia  it  is  inexcusable  to-day  to  fail  in 
differentiating  the  malarial  fevers  from  typhoid  fever. 

Yellow  Fever. — In  regions  in  which  both  malaria  and  yellow  fever  are 
endemic  the  differentiation  of  these  diseases  is  often  exceedingly  difficult  with- 
out a  blood  examination,  and  pernicious  cases  of  aestivo-autumnal  fever  are  not 


[34      DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 


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DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       335 

infrequently  mistaken  for  yellow  fever.  This  is  especially  true  of  the  so-called 
bilious  remittent  and  haemorrhagic  forms  of  pernicious  malaria,  in  which  the 
yellow  tint  of  the  skin,  the  congested  eyes,  the  flushed  cheeks,  the  severe  vomit- 
ing, often  of  black  fluid  resembling  the  dreaded  "black  vomit,"  the  high  tem- 
perature, and  the  not  infrequent  occurrence  of  albumin  in  the  urine,  form  a 
clinical  picture  closely  resembling  that  of  yellow  fever.  A  patient  presenting 
such  a  picture  in  a  yellow  fever  region  is  almost  always  thought  to  be  suffering 
from  that  disease,  and  in  such  cases  the  examination  of  the  blood  is  of  the  very 
greatest  importance. 

Kala-Azar. — The  differentiation  of  kala-azar  and  the  malarial  fevers  is 
of  interest  and  importance,  as  kala-azar  was  for  years  considered  a  chronic 
form  of  malarial  infection,  and  only  with  the  discovery  of  the  Leishmania- 
donavani  was  the  distinction  recognized  and  the  differentiation  of  the  two 
diseases  made  possible.  In  kala-azar  we  have  an  enlarged  spleen,  anaemia, 
an  irregular  temperature  curve  similar  to  that  of  many  cases  of  aestivo-aulum- 
nal  malaria;  and  an  examination  of  the  blood  will  alone  enable  us  to  be  sure  of 
our  diagnosis. 

Dengue. — The  malarial  fevers  may  be  confused  with  dengue  fever,  but  in 
the  latter  disease  the  more  severe  character  of  the  muscular  pains  and  the 
occurrence  of  an  eruption  will,  in  most  cases,  serve  to  distinguish  the  two.  An 
examination  of  the  blood  is  often  necessary,  however,  and  should  never  be 
neglected. 

Malta  Fever. — In  regions  in  which  Malta  fever  occurs  there  is  often  much 
difficulty  in  differentiation  between  this  disease  and  the  more  atypical  forms  of 
the  aestivo-autumnal  fevers.  An  examination  of  the  blood  will  at  once  demon- 
strate the  plasmodia  if  malarial  infection  be  present,  and  a  positive  reaction  will 
be  obtained  from  the  blood  with  the  agglutination  test  with  Micrococcus  meli- 
tensis,  if  Malta  fever  be  present. 

Other  Fevers. — Among  the  numerous  other  febrile  processes  often  mis- 
taken for  malaria  may  be  mentioned  puerperal  fever,  which  has  already  been 
discussed;  septicaemia  and  pyaemia,  in  which  the  chills,  occurring  at  regular 
intervals,  followed  by  fever  and  sweating,  often  produce  a  picture  very  suggestive 
of  malarial  fever;  pyelitis  attended  by  chills  and  fever;  the  early  stages  of  the 
eruptive  fevers;  relapsing  fever,  in  which  the  demonstration  of  the  spirochaetae 
in  the  blood  is  sufficient  to  establish  the  diagnosis,  and  trypanosomiasis ,  which 
depends  for  its  diagnosis  upon  the  demonstration  in  the  blood  of  Trypanosoma 
gambiense.  All  of  these  conditions  may  be  easily  differentiated  from  the 
malarial  fevers  by  a  careful  microscopical  examination  of  the  blood. 

Tuberculosis. — Many  cases  of  tuberculosis,  especially  if  complicated  by 
a  streptococcus  infection,  exhibit  a  temperature  curve  closely  resembling  that  of 
a  double  tertian  or  a  quotidian  aestivo-autumnal  infection,  and  there  may  also  be 
daily  chills  or  chilly  sensations,  while  the  patient  presents  the  anaemia  and  the 
facies  so  often  observed  in  long-continued  malarial  infections.  There  is  no 
enlargement  of  the  spleen,  however,  and  an  examination  of  the  chest  will  show 


56 


6       DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 


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DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       337 

lesions  not  found  in  malaria.  The  examination  of  the  blood  for  the  malarial 
Plasmodia  and  of  the  sputum  for  Bacillus  tuberculosis  will  definitely  establish 
the  diagnosis.  Not  very  rarely  cases  of  tuberculosis  are  complicated  by  some 
form  of  malarial  infection,  and  thus  an  examination  of  the  blood  is  of  great 
importance,  as  the  discovery  of  the  malarial  infection  and  its  removal  will 
greatly  benefit  the  patient.  Such  cases  are  usually  stumbled  upon  accidentally 
while  examining  the  blood  of  tubercular  patients  for  leucocytosis,  but  it  should 
be  a  routine  practice,  in  malarial  regions,  to  examine  the  blood  of  all  tubercular 
patients,  presenting  chills  and  a  temperature  above  ioo°  F.,  for  the  malarial 
Plasmodia.     (Chart  No.  20.) 

Hepatic  Abscess. — In  regions  where  amoebic  dysentery  is  endemic,  cer- 
tain patients  suffering  from  hepatic  abscess  due  to  the  amoebae  may  present 
symptoms  which  closely  simulate  those  of  malarial  fever;  thus,  there  may  be 
chills  occurring  at  daily  intervals,  and  a  temperature  curve,  which,  while  that  of 
sepsis,  very  closely  simulates  that  of  some  of  the  forms  of  aestivo-autumnal 
malaria.  The  chief  clinical  points  in  favor  of  hepatic  abscess  are  enlarge- 
ment of  the  liver  and  tenderness  over  the  hepatic  region,  while  the  spleen  is  not 
enlarged;  the  occurrence  of  very  profuse  perspiration,  independently  of  the 
decline  of  the  fever,  and  the  history  of  dysentery.  An  examination  of  the  blood 
will  establish  the  diagnosis  of  malaria  by  the  finding  of  the  plasmodia,  while  in 
those  cases  in  which  the  symptoms  are  suggestive  of  a  chronic  malarial  infection, 
the  absence  of  plasmodia  or  pigmented  leucocytes  and  the  presence  of  a  leuco- 
cytosis would  point  to  the  presence  of  hepatic  abscess.  I  have  observed  more 
than  one  case  in  which  autopsy  showed  the  presence  of  multiple  abscesses  in 
the  liver  of  patients  diagnosed  and  treated  for  malaria,  so  that  this  mistake 
is  one  that  is  frequently  made  and  one  that  should  be  carefully  guarded 
against. 

Ulcerative  Endocarditis. — The  temperature  curve  in  ulcerative  endocar- 
ditis often  resembles  that  of  a  quotidian  malaria,  while  there  may  be  present 
paroxysms  of  chill,  fever,  and  sweating.  Dock  has  published  a  very  interesting 
case  of  this  kind,  the  chart  of  which  is  here  reproduced.  (Chart  No.  21.) 
Examination  of  the  heart  will  generally  suffice  to  determine  the  nature  of  such 
cases,  and  if  not,  an  examination  of  the  blood  will  generally  settle  the  question 
at  once. 

Dysentery. — As  has  been  shown,  malarial  infection  may  occur  with 
dysentery,  and  the  removal  of  the  malarial  element  in  a  large  proportion  of  such 
cases  results  in  a  rapid  improvement  in  the  dysenteric  symptoms  and  their  final 
disappearance.  In  view  of  this  fact,  i.e.,  that  malarial  infection  is  capable  of 
producing  the  clinical  symptoms  of  dysentery,  it  is  important  that  we  be  able  to 
differentiate  between  these  cases  and  true  cases  of  dysentery,  either  amoebic 
or  specific.  The  examination  of  the  blood  and  of  the  faeces  should  quickly  enable 
us  to  differentiate  dysentery  and  the  malarial  fevers,  and  such  an  examination 
is  most  useful  also  in  that  it  will  often  result  in  demonstrating  a  combination  of 
the  two  diseases. 


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8       DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 


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DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       339 

Cerebral  Apoplexy. — The  differential  diagnosis  between  cerebral  apoplexy 
and  some  forms  of  pernicious  malaria,  such  as  the  comatose  form,  is  often 
extremely  difficult  without  a  blood  examination.  Cerebral  pernicious  malaria 
is  often  manifested  by  coma,  stertorous  breathing,  loss  of  reflexes,  and  other 
symptoms  which  so  closely  simulate  apoplexy  that  a  clinical  diagnosis  is  almost 
impossible.  The  main  clinical  points  to  be  relied  upon  in  differentiating  the 
two  are  the  high  fever  in  malaria,  although  this  is  not  constant;  the  age  of  the 
patient,  and  the  presence  of  splenic  enlargement  if  the  cause  be  malarial.  An 
examination  of  the  blood  should  be  made  at  once  in  all  cases  of  sudden  loss  of 
consciousness  in  malarial  regions. 

Sunstroke. — In  tropical  or  subtropical  regions  certain  cases  of  pernicious 
malaria  very  closely  simulate  sunstroke.  I  have  already  described  such  cases 
and  have  spoken  of  the  fact  that  heat  very  often  aggravates  or  brings  on  severe 
malarial  paroxysms.  It  is  therefore  necessary  that  we  be  sure  that  an  apparent 
case  of  sunstroke  is  not  in  reality  a  case  of  pernicious  malarial  fever,  and  a 
microscopic  examination  of  the  blood  is  our  only  means  of  assuring  ourselves 
of  this  fact.  I  can  recall  three  instances  in  which  men  were  brought  to  the 
hospital  supposed  to  be  suffering  from  sunstroke,  whose  blood,  when  examined, 
was  found  to  be  teeming  with  malarial  plasmodia.  The  history  of  no  previous 
attacks  of  malaria;  the  lack  of  anaemia;  and  the  absence  of  splenic  enlarge- 
ment will  aid  us  in  arriving  at  a  diagnosis  of  sunstroke,  but  an  examination  of 
the  blood  should  never  be  neglected. 

Among  other  disease  processes  which  may  be  confused  with  malaria  may  be 
mentioned  cholera,  in  which  the  diagnosis  rests  upon  a  blood  examination; 
disease  of  the  gall-bladder  and  bile-ducts,  if  suppurative;  lobar  and  lobular 
pneumonia;  WeiVs  disease;  purpura  haemorrhagica,  anduraemia.  A  microscopi- 
cal examination  of  the  blood  will  suffice  to  differentiate  the  malarial  fevers  from 
any  of  these  conditions. 

Leukaemia. — In  very  rare  instances  the  malarial  fevers  may  be  confused 
with  leukaemia,  as  in  the  latter  disease  chills  and  fever  frequently  occur,  and 
more  or  less  anaemia  is  present.  Very  rarely  leukaemia  is  complicated  by 
malaria  and  a  microscopical  examination  of  the  blood  will  result  in  a  diagnosis  of 
both  diseases.  I  have  records  of  a  most  interesting  case  of  this  kind  in  the 
person  of  a  young  soldier  who  entered  the  hospital  for  the  first  time,  suffering 
from  a  chill  and  a  temperature  of  1030  F.  The  blood  was  sent  to  the  laboratory 
for  examination  for  malaria,  and  was  found  to  present  the  typical  picture  of 
myeloid  leukaemia,  but  upon  a  hasty  examination  no  malarial  plasmodia  were 
found.  However,  a  blood  count  showing  1,520,000  leucocytes  per  cu.  mm.  and 
only  410,000  red  cells  per  cu.  mm.  indicated  a  more  careful  examination  of  the 
blood,  which  resulted  in  finding  numerous  tertian  plasmodia,  thus  proving  that 
the  symptoms  present  were  indeed  malarial  in  character,  and  that  the  patient 
was  in  addition  suffering  from  leukaemia,  which  had  not  been  suspected.  The 
spleen  in  this  case  reached  to  the  umbilicus,  but  had  never  occasioned  the  man 
any  trouble.     The  very  great  reduction  in  the  red  corpuscles  is  of  interest,  being 


34°       DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 

produced  by  the  combined  action  of  the  leukaemia  and  the  plasmodia.     The 

elimination  of  the  malarial  infection  resulted  in  a  rise  of  the  red  blood  count  to 
over  2,000,000  cells  per  cu.  mm. 

It  is  from  the  study  of  such  cases  as  this  that  we  realize  the  importance  of  a 
blood  examination  in  every  febrile  condition,  and  with  the  improvement  in  our 
microscopical  methods,  the  reduction  in  the  cost  of  microscopes,  and  the  op- 
portunities given  every  physician  to  master  the  technic  of  blood  examinations, 
it  may  be  truly  said  that  he  who  to-day  loses  a  patient  from  malarial  fever  be- 
cause of  inability  to  recognize  the  disease,  bears  upon  his  shoulders  a  heavy 
weight  of  responsibility  which  no  regret  will  lessen. 


Literature  upon  the  Laboratory  and  Clinical  Diagnosis  of  the  Malarial  Fevers. 
Literature  upon  Staining  Methods. 

1888.      Chenzinsky    Lehre    liber    den     Microorganismus     des     Malaria- fiebers. 

Centralbl.  f.  Bakt.  Referat.  iii,  No.  15,  p.  457. 
1 89 1.      Romano wsky.      Zur   Frage    der  Parisitologie  u.  Therapie   der   Malaria. 

St.  Peters.      Med.  Woch.,  Nos.  34  and  35. 

1897.  M anson,  P.  A.      Method  of  Staining  the  Malaria  Flagellated  Organism. 
Brit.  Med.  Jour.,  vol.  ii,  p.  68. 

1898.  Nocht.     Zur  Farbung  des  Malariaparasites.     Centralbl.   f.    Bakt.,    Bd. 
xxiv,  No.  1,  p.  8. 

1898.      Zieman,  H.      Eine    Methode    der    Doppelfarbung    bei    Flagellaten,   etc. 
Centralbl.  f.  Bakt.,  Bd.  xxiv,  No.  25,  p.  945. 

1898.  Idem.      Ueber  Malaria  und  andere  Blutparasiten.     Jena. 

1899.  Nocht.     Farbung  der  Malariaparasiten.     Centralbl.  f.  Bakt.,   Bd.  xxv, 
No.  1,  p.  17. 

1901.  Ewing.      Malarial  Parasitology.      Jour.  Exper.  Med.,  vol.   v,   No.    5,  429. 

1902.  Giemsa.      Farbenmethoden  fiir   Malariaparasiten.      Centralbl.    f.   Bakt., 
Bd.  xxxii,  No.  4,  p.  307. 

1902.      Craig,   C.   F.      A   New   Method  of   Staining  the  Malarial  Parasites,  etc. 
N.  Y.  Med.  Jour.,  Sept.  13. 

1902.  Wright,  J.  H.     A  Rapid  Method  for  the  Differential  Staining  of  Blood 
Films  and  Malarial  Parasites.     Jour,  of  Med.  Research,  vol.  vii,  No.  1. 

1903.  Laveran.     Procede  de  coloration  des  Protozoaires  parasites  du  sang. 
Compt  rendus.  de  la  Soc.  de  Biol.,  March  7. 

1904.  Leishman.      Notes  on  Romanowsky  Staining.  Jour.   R.  A.  Med.  Corps, 
vol.  ii,  p.  669. 

1904.      Idem.      Deep  Chromatin   Staining    in    Malaria.      The    Lancet,    Mar.    19, 
p.  801. 

1904.  Giemsa.       Meine      Methylenazur-Methylenblau-Eosin      Farbenmethode. 
Centralbl.  f.  Bakt.,  Bd.  xxxvii,  No.  2,  p.  308. 

1905.  Harris,  H.  F.      A  Modification  of  the  Romanowsky  Stain.      Centralbl. 
f.  Bakt.,  Bd.  xxxix,  No.  2. 

1904.  Plehn,  A.      Schnellfarbung     und     Schnittfarbung    nach    Romanowsky. 
Arch.  f.  Schiffs-  und  Tropenhyg,  Bd  viii,  Heft  2. 

1905.  Leishman.     A   Method  of  Producing  Chromatin   Staining  in  Sections. 
Jour,  of  Hygiene,  vol.  iv,  No.  3. 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       34I 

General  Literature  upon  Diagnosis. 

1899.  Curry,  J.  J.  On  the  Value  of  Blood  Examinations  in  the  Diagnosis  of 
Camp  Fevers.      Boston  Med.  and  Surg.  Jour.,  vol.  cxii,  p.  513. 

1900.  Kronecker.  Die  "Kala-azar"  in  der  vorderindischen  Provinz  Assam. 
Archiv.  f.  Schiffs-  und  Tropenhyg,  Bd.  iv,  No.  4,  p.  220. 

1900.  Manson,  P.     The  Diagnosis  of  Malaria,  etc.     The  Lancet,  vol.  i,  p.  1377. 

1901.  Grixoni.  L'agglutinazione  del  sangue  malarico.  Gazz.  degl.  Osped.  e 
delle  cliniche,  Anno  xxii,  No.   57. 

1900.  Stephens  and  Christophers.  The  Agglutination  of  Sporozoites.  Roy. 
Soc.  Rep.  on  Malaria,  3d  Series. 

1 90 1.  Rogers,  L.  Note  on  Serum  Reactions  and  the  Temperature  Curve 
in  Chronic  Malaria,  including  Kala-azar.      Ind.  Med.  Gaz.,  p.  377. 

1 90 1.  Idem.  The  Diagnostic  Value  of  the  Variations  in  the  Leucocytes  and 
other  Blood  Changes.      Brit.  Med.  Jour.,  April  5,  p.  827. 

1901.  La  Monaco  e  Panichi.  Agglutination  of  the  Blood  in  Malaria.  II 
policlinico,  vol.  viii. 

1 90 1.  Crespin.  Diagnostic  entre  la  malaria  et  la  fievre  jaune,  etc.  Bull,  de 
medicine  sanitaire  maritime. 

1902.  La  Monaco  e  Panichi.  Agglutination  of  Malarial  Blood.  Second  Note. 
Reforma  Medica,  Nos.  33-35. 

1903.  Laveran.  Pseudo-hematozoaires  endoglobulaires.  Compt.  rendus  de 
la  Soc.  Biologie,  No.  14. 

1903.  Craig,  C.  F.  Malarial  Infections:  Their  Parasitology,  Symptomatology, 
Diagnosis  and  Treatment.      International  Clinics,  Oct,  1903,  p.  1. 

1904.  Klemperer.  Ueber  Fieber  bei  Syphilis  der  Leber.  Zeitschr.  f.  klin. 
Med.,  Bd.  Iv. 

1904.     Powell,  A.      The  Blood  Examination  of  Three  Thousand  Four  Hundred 

Cases  of  Febrile  Disease  in  Bombay.      Ind.  Med.  Gaz.,  Nos.  2  and  3. 
1904.      Hunt,  W.  J.      Interesting  Cases  of  Malaria  which  Simulated  Appendicitis. 

N.  Y.  State.  Jour,  of  Med.,  vol.  iv. 
1904.      Capograssi,   A.      Valore   diagnostico   del  potere   agglutinante   del   siero 

del  sangue  di  malarici  sui  globuli  rossi.      Atti.  della  Soc,  per   gli   Studi 

della  Malaria,  p.  65. 

1907.  Daniels.      Laboratory  Studies  in  Tropical  Medicine.      London. 

1908.  Stephens  and  Christophers.  The  Practical  Study  of  Malaria  and 
other  Blood  Parasites.      London. 


CHAPTER  III. 
The    Prophylaxis  of  the  Malarial  Fevers. 

The  subject  of  prophylaxis  in  the  malarial  fevers  is  of  the  very  greatest 
importance,  for  these  fevers  are  preventable,  and  since  the  discovery  of  the 
Plasmodia  and  the  method  of  the  transmission  of  these  parasites  by  the  mosquito, 
we  are  in  a  position  to  control  the  spread  of  fevers  of  malarial  origin.  Until 
recently  we  were  ignorant  of  the  source  of  the  infection  in  malaria  and  could  do 
but  little  toward  prevention,  but  we  now  know  the  etiological  factors  concerned 
in  the  production  of  the  malarial  fevers  and  their  method  of  transmission,  and 
we  also  know  that  proper  methods  of  prophylaxis  have  already  resulted  in  the 
disappearance  of  the  infection  from  numerous  localities.  It  is  not  too  much  to 
believe  that,  in  time,  the  malarial  fevers  will  be  as  rare  as  are  now  some  of  the 
acute  infectious  fevers,  provided  we  maintain  and  extend  the  present  prophy- 
lactic methods  in  use  against  this  class  of  fevers. 

Man  and  mosquitoes  are,  so  far  as  we  know,  the  only  sources  of  malarial 
infection,  and  the  mosquitoes  have  to  become  infected  from  man;  it  therefore 
follows  that  if  it  were  possible  to  destroy  all  mosquitoes  capable  of  transmitting 
malaria  or  to  destroy,  all  plasmodia  infecting  man,  we  would  be  able  to  cause 
the  disappearance  of  these  fevers,  but  as  this  is  impossible,  we  must  depend  in 
prophylaxis  on  methods  directed  both  toward  the  destruction  of  the  mosquito 
and  the  destruction  of  the  plasmodia,  remembering  that  while  it  will  be 
given  us  in  many  instances  practically  to  rid  certain  localities  of  malaria,  in 
many  others  the  most  that  we  can  hope  for,  because  of  local  conditions,  is  a 
distinct  reduction  in  the  number  of  cases.  The  success  of  malarial  prophylaxis 
is  very  largely  a  question  of  local  conditions  and  the  assistance  given  by  the 
local  and  governmental  authorities. 

The  prophylactic  methods  at  present  in  use  against  malaria  consist  in: 

i.  The  prevention  of  the  development  of  the  plasmodia  in  man  and  the 
destruction  of  the  plasmodia  in  infected  individuals.  Both  these  aims  are 
accomplished  by  the  administration  of  quinine,  i.  e.,  quinine  prophylaxis. 

2.  Destruction  of  the  mosquitoes  transmitting  malaria. 

3.  Protection  of  man  from  the  bites  of  mosquitoes. 

4.  Education  of  the  public  regarding  malarial  prophylaxis. 

In  order  to  be  most  successful  all  of  the  methods  mentioned  should  be 
employed  in  prophylaxis,  although  in  certain  localities  it  may  be  found  possible 
to  achieve  success  by  attention  only  to  mosquito  destruction  or  to  quinine 
prophylaxis,  while  in  others  we  may  have  to  rely  chiefly  upon  quinine  pro- 
phylaxis   because   of   the   manifest   impossibility  of  destroying  the   breeding- 

342 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       343 

places  of  mosquitoes.  If  possible,  however,  we  should  employ  all  of  the  methods 
of  prophylaxis  mentioned,  as -by  so  doing  we  will  more  quickly  attain  a  successful 
result. 

1.  The  Destruction  of  the  Plasmodia. — It  is  obvious  that  if  we  can 
destroy  the  plasmodia  in  infected  individuals  or  prevent  their  development 
we  will  be  successful  in  preventing  malaria,  as  it  will  be  impossible  for  mosqui- 
toes biting  such  individuals  to  become  infected.  This  fact  is  the  basis  of  quinine 
propyhlaxis,  which  consists  in  the  administration  of  the  drug  to  all  individuals 
harboring  the  plasmodia  and  to  all  individuals  exposed  to  the  bites  of  mosquitoes 
belonging  to  the  Anophelina.  We  know  that  quinine  is  capable  of  destroying 
the  malarial  plasmodia  in  the  blood  of  man  and  that  it  is  most  effective  in  the 
younger  stages  of  development  of  these  parasites,  but  that  in  all  stages,  with  the 
exception  of  the  gametes,  it  is  capable  of  interfering  with  the  life  cycle  in  the 
human  body  and  eventually  destroying  it.  The  fact  that  quinine  has,  so  far 
as  we  know,  no  effect  upon  the  crescentic  gametes  of  the  aestivo-autumnal 
infections,  and  probably  none  upon  the  gametes  of  tertian  and  quartan  infec- 
tions, renders  quinine  prophylaxis  uncertain  and  makes  it  essential  that  we  also 
direct  our  methods  toward  the  destruction  of  the  mosquito. 

The  advocates  of  quinine  prophylaxis,  such  as  Koch,  have  claimed  that 
by  this  method  alone  it  is  possible  to  rid  a  community  of  malaria,  but  prac- 
tically this  can  only  be  true  in  very  exceptional  localities,  where  the  universal 
use  of  the  drug  can  be  enforced.  That  such  enforcement  would  eventually 
render  the  occurrence  of  malaria  impossible  is  undoubtedly  true,  as  the  develop- 
ment of  the  sporozoites  inoculated  by  mosquitoes  would  be  rendered  impossible 
by  the  prophylactic  dose  of  quinine,  and  no  new  mosquitoes  could  become 
infected.  In  addition,  those  already  infected  would  be  harmless.  As  a  matter 
of  fact,  however,  such  results  could  only  be  obtained  by  the  administration  of 
quinine  for  a  long  period  of  time  to  every  individual  in  the  infected  locality, 
and  the  prophylactic  use  of  the  drug  would  have  to  be  continued  indefinitely, 
for  as  long  as  Anopheles  mosquitoes  are  present  so  long  is  there  danger  of  the 
spread  of  malarial  infection  from  imported  cases  of  the  disease.  While  it 
is  unwise,  as  has  been  shown  by  experience,  to  depend  wholly  upon  quinine 
prophylaxis,  it  is  a  fact  that  the  use  of  the  drug  in  this  manner  is  of  the  greatest 
value  and  should  never  be  neglected.  This  method  has  now  been  tried  for 
years  and  the  data  on  hand  concerning  its  efficiency  prove  conclusively  that 
it  is  of  prime  importance  in  the  prevention  of  the  malarial  fevers. 

The  authorities  differ  as  to  the  dose  of  quinine  to  be  administered  in 
prophylaxis  and  the  best  time  for  its  administration.  Koch  believes  in  using 
1  gm.  (15  grains)  administered  upon  every  eighth  and  ninth  day;  Laveran, 
0.4  to  0.6  gm.  every  12  days;  A.  Plehn,  1  gm.once  a  week;  Laborde,  0.1  to  0.3  gm. 
daily;  and  Zieman  advocates  1  gm.  given  upon  every  fourth  day.  The  method 
recommended  by  Koch  has  been  adopted  by  many  observers.  He  claims  to 
have  secured  better  results  by  it  than  by  any  other  method,  and  at  Stephensort, 
New  Guinea,  he  claims  that  he  was  able  to  entirely  rid  the  place  of  malaria  by 


344       DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 

his  method  alone.  Frosch,  in  Istria,  found  that  whereas  16  per  cent,  of  the 
inhabitants  were  infected  before  the  use  of  Koch's  method  (407  infections), 
one  year  after  the  initiation  of  the  method  there  were  only  1 7  new  infections,  and 
a  year  after  that  there  were  none.  Gosio,  in  Toskano,  Italy,  reports  a  decrease 
in  the  malarial  morbidity  from  47  per  cent,  to  12  per  cent,  with  this  method  alone 
after  two  years'  trial.  In  South  Africa,  Vagedes  began  Koch's  method  in  the 
summer,  the  fever-free  season.  As  a  result  he  found  a  great  decrease  in  the 
number  of  cases  of  malaria  during  the  next  malarial  season.  Thus,  in  Tutara, 
where  the  previous  year,  before  the  use  of  Koch's  method,  there  had  been  a 
morbidity  of  75  per  cent.,  this  season  there  was  a  morbidity  of  only  7  per  cent.; 
in  Kanas,  previous  year  a  morbidity  of  30  per  cent.,  this  year  none;  in  Franz- 
fontain,  previous  year  a  morbidity  of  75  per  cent.,  this  year  only  9  per  cent. 

Other  authorities  have  not  secured  as  good  results  with  this  method  as 
with  the  daily  administration  of  quinine  in  smaller  doses  or  administered  in 
larger  doses  at  more  frequent  intervals.  Ollwig  has  shown  that  in  uncivilized 
communities,  such  as  Dutch  East  Africa,  such  a  method  as  Koch's  is  impracti- 
cable as  it  is  impossible  to  administer  quinine  to  all  of  the  inhabitants,  or  even 
to  all  who  harbor  the  malarial  plasmodia.  Zieman  considers  the  method  use- 
ful but  not  to  be  depended  upon  alone,  and  this  opinion  is  also  held  by  Manson 
and  A.  Plehn.  In  considering  the  results  attained  by  those  who  advocate  the 
method  of  Koch,  it  should  be  remembered  that  the  percentage  of  malarial 
infections  varies  very  greatly,  even  in  badly  infected  regions,  from  year  to  year, 
and  also  that  the  success  of  the  method  depends  upon  how  many  of  the  inhabi- 
tants of  a  given  locality  have  the  resistant  gametes  in  their  blood,  and  the 
number  and  species  of  the  Anophelinae  present. 

Zieman  recommends  the  administration  of  quinine  as  a  prophylactic  in 
doses  of  1  gram  every  fourth  day,  and  if  quinine  be  disagreeable  in  its  effects 
that  euquinine  in  doses  of  1  gram  be  substituted.  He  has  shown  that  by  the 
use  of  this  method  not  only  is  the  number  of  new  infections  greatly  reduced, 
but  that  haemoglobinuria  is  not  so  apt  to  occur  in  those  taking  the  quinine  as 
it  is  in  those  who  have  not  taken  the  drug.  Zieman  does  not  believe  that  in 
regions  where  pernicious  forms  of  malaria  occur  Koch's  method  is  sufficient, 
as  he  claims  that  the  dose  of  quinine  is  too  small  if  given  only  upon  the  eighth 
and  ninth  days. 

Duncan,  from  his  experience  in  the  prophylactic  use  of  quinine  in  large  mili- 
tary commands,  concludes  that  quinine,  in  daily  doses  of  0.2  grm.  to  0.6  grm., 
reduces  the  admissions  to  hospital  from  malaria  over  one-half,  and  in  regions 
where  only  tertian  and  quartan  infections  are  found,  I  have  demonstrated  that 
daily  doses  of  0.15  grm.  of  quinine  are  sufficient  to  prevent  malarial  infection  in 
the  vast  majority  of  instances.  At  Camp  Stotsenburg,  in  the  Philippine 
Islands,  where  nearly  36  per  cent,  of  the  command,  a  regiment  of  cavalry, 
entered  the  hospital  with  malaria  during  the  malarial  season,  I  recommended 
the  prophylactic  use  of  quinine,  the  drug  being  administered  every  seventh  day 
in  doses  of  1  grm.     This  method  was  used  for  several  months  and  resulted  in  a 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       345 

diminution  of  over  two-thirds  in  the  malarial  infections  entering  the  hospital. 
At  this  post  every  other  prophylactic  method  was  used  previously  to  the  use  of 
the  quinine,  such  as  destruction  of  mosquitoes,  use  of  mosquito  bars,  etc.,  but 
only  when  to  these  methods  was  added  the  prophylactic  use  of  quinine  did  we 
secure  the  fullest  measure  of  success  in  combating  malaria.  Since  using  the 
method  of  quinine  porphylaxis  I  have  found  that  the  best  results  are  secured 
by  administering  the  drug  in  doses  of  0.6  grm.  (10  grains)  upon  retiring,  every 
third,  sixth,  and  ninth  days  for  two  weeks,  and  then  the  same  amount  upon 
every  fifth  day  thereafter.  The  object  of  giving  the  drug- more  frequently  for  a 
period  of  two  weeks  is  to  destroy  any  plasmodia  that  might  have  been  present 
at  the  time  the  quinine  prophylaxis  is  instituted. 

The  most  important  contribution  to  the  subject  of  quinine  prophylaxis 
has  been  given  us  by  Celli,  as  the  result  of  the  work  of  the  Italian  Society  for 
the  Study  of  Malaria.  He  states  that  in  Italy  it  has  been  found  prac- 
tically impossible  to  prevent  recurrences  in  all  malarial  infections,  and  that, 
therefore,  it  is  necessary  to  prevent  the  malarial  infection  itself.  In  order  to 
do  this  he  relies  mostly  upon  quinine  prophylaxis,  although  all  the  other  methods 
of  prophylaxis  are  used  faithfully  by  the  society.  As  the  result  of  their  ex- 
perience he  believes  in  the  daily  administration  of  quinine  as  a  prophylactic, 
in  average  doses — 0.4  gm.  of  the  bisulphate,  hydrochlorate,  or  bihydrochlorate 
to  adults;  0.2  gm.  of  the  same  salts  for  children,  or  0.3  gm.  of  the  tannate  of 
quinine,  in  all  cases  compounded  with  sweet  chocolate,  thus  disguising  the 
bitter  nauseating  taste.  Where  the  malarial  infections  are  of  very  severe  char- 
acter he  recommends  the  daily  administration  of  0.5  to  0.6  gm.  Celli  says: 
"He  who  takes  quinine  every  day,  and  therefore  has  always  a  supply  of 
quinine  in  the  blood  stream,  can  undergo  with  impunity  inoculations  of  blood 
full  of  malarial  parasites,  and  can  expose  himself  with  little  or  no  danger  to 
the  bites  of  infected  mosquitoes." 

He  also  says:  "  The  unanimous  agreement  of  both  the  doctors  and  patients 
during  these  last  years  have  convinced  us  more  and  more  that  this  daily  quinine 
treatment  diminishes  notably  the  recurrences,  causes  the  perniciousness  to  dis- 
appear, prevents  cachexia,  and  very  frequently  the  primary  infections,  and  at 
least  renders  the  fevers  milder  and  more  readily  curable  by  simply  increasing 
the  quinine  for  a  few  days  to  the  therapeutic  dose  and  then  returning  to  the 
prophylactic  dose." 

"Hence  it  is  that  from  the  Agro  Romano,  where  we  made  our  first  experi- 
ments, the  daily  use  of  quinine,  which  is  as  necessary  as  daily  bread  in  the  dis- 
tricts and  months  of  malaria,  has  to-day  extended  to  every  malarious  province  of 
Italy,  and  it  is  extending  more  and  more  among  the  rural  populations,  the  State 
employes  living  along  the  railways,  and  in  the  army.  Thus  in  Italy  (where  we 
have  employed  it  from  1899),  Algeria,  and  Russia  it  has  been  proved  to  be  the 
most  suitable  method  for  guaranteeing  health  and  the  power  of  work  to  man 
even  in  the  most  desolate  malarious  regions." 

These  eloquent  words  of  Celli  speak  conclusively  of  the  value  of  quinine 


546       DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 


prophylaxis  in  malaria,  but  it  is  only  because  the  Government  supported 
the  Italian  Society  by  the  state  issue  and  sale  of  quinine  that  such  results 
have  been  possible.  Thus  in  Italy  the  state  sells  quinine  to  those  who  can 
afford  to  pay  for  it,  at  the  minimum  price;  workers  of  every  kind  have  quinine 
issued  to  them  gratuitously  for  the  treatment  of  malaria,  at  the  expense  of  their 
employers;  workers  of  every  kind  have  quinine  issued  to  them  gratuitously  for 
prophylaxis,  at  the  expense  of  the  State;  and,  finally,  the  poor  have  quinine 
given  them  gratuitously.  As  Celli  says,  these  laws  conflicted  with  many  private 
interests,  but  were,  nevertheless,  enforced,  and  to-day  Italy  has  the  honor  of 
pointing  out  to  the  world  the  proper  legislative  control  of  a  disease  that  has 
made  her  lands  barren  in  the  past  and  has  destroyed  countless  thousands 
of  her  inhabitants. 

The  following  table,  given  by  Celli,  illustrates  the  results  obtained  by 
quinine  prophylaxis  in  Italy,  and  also  demonstrates  that  the  state  has  profited 
not  only  by  the  saving  of  the  lives  of  thousands  of  its  citizens,  but  also  finan- 
cially. It  should  be  stated  that  the  profit  made  by  the  state  from  the  sale  of 
quinine  is  expended  in  the  prevention  of  malaria  in  other  ways,  as  in  drainage 
works,  etc. 

State  Quinine  and  Mortality  from  Malaria. 


Consumption  of  state  quinine 

Mortality  from  malaria 

Net   profit    of   ad- 

ministration 

of   state    quinine 

Financial   year 

Kilograms  sold 

Solar  year 

Deaths 

in  lire 

1895 

0 

189S 

16464 

0 

1896 

0 

1896 

14071 

0 

1897 

0 

1897 

11947 

0 

1898 

0 

1898 

11378 

0 

1899 

0 

1899 

1081 1 

0 

190c 

0 

1900 

15865 

0 

1901 

0 

1901 

13861 

0 

1902-3 

2242 

1902 

9908 

34270 

1903-4 

7234 

1903 

8513 

183039 

1904-5 

14071 

1904 

8501 

183382 

1905-6 

18712 

1905 

7838 

293395 

1906-7 

20723 

1906 

4871 

462290 

The  above  table  shows  that  while  from  1895  to  1902  an  average  of  13,000 
individuals  died  annually  in  Italy  from  the  malarial  fevers,  since  the  introduc- 
tion of  quinine  prophylaxis  in  1902  the  mortality  has  steadily  declined  until  in 
1906  it  was  less  than  5,000  per  annum.  Who  can  doubt  the  efficacy  of  this 
method  of  prophylaxis  when  such  evidence  as  this  is  presented  and  how  small 
any  pecuniary  out-lay  would  be,  placed  beside  the  thousands  of  lives  which 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       347 

have  been  saved  by  the  free  distribution  of  quinine  in  Italy.  It  is,  however, 
cheering  to  observe  that  the  state  has  profited  financially  through  the  sale  of  the 
drug  to  those  able  to  buy,  and  that  in  reality  thousands  of  lives  have  been  saved 
at  actually  no  expense  to  the  state.  The  experience  of  Italy  well  illustrates 
the  fact  that  no  state  can  stand  to  lose  financially  by  caring  for  the  health  of  its 
inhabitants. 

Celli  claims  that  the  issue  of  quinine  in  1905  saved  no  less  than  7,500  lives, 
and  he  states  that  of  59,340  persons  taking  daily  doses  of  four  centigrams  of 
quinine,  only  5.8  per  cent,  developed  malaria,  including  both  initial  infections 
and  relapses.  In  the  south  of  Italy,  where  malaria  is  most  severe,  the  per- 
centage of  infections  has  been  reduced  from  80  per  cent,  to  18  per  cent. 

Bettinetti,  in  the  commune  of  Milan,  used  daily  doses  in  3,453  cases,  of 
whom  only  4  per  cent,  developed  malaria,  and  Brignoni  and  Algona  found  that 
by  using  as  small  a  daily  dose  as  20  centigrams  they  were  able  to  prevent  in- 
fection in  most  of  those  experimented  upon.  Thus  of  80  persons  who  took  this 
daily  dose  none  developed  malaria,  while  of  175  who  took  the  same  dose  at  ir- 
regular intervals,  13  developed  the  fever.  Of  50  individuals  who  did  not  take 
any  quinine,  31  developed  malarial  infections.  From  the  evidence  adduced  I 
believe  that  it  is  impossible  to  deny  that  quinine  prophylaxis  in  malaria  is  of  the 
greatest  value,  but  it  should  be  remembered  that  we  cannot  depend  upon  this 
method  alone,  except  in  very  exceptional  instances,  and  even  those  who  have 
used  it  most  extensively  have  also  used  the  other  prophylactic  methods  known  to 
be  of  service,  such  as  destruction  of  the  mosquitoes,  protection  from  mosquito 
bites  by  screening,  isolation  of  malarial  cases,  and  avoidance  of  notoriously 
infected  regions.  It  is  not  too  much  to  say,  however,  that  unless  quinine 
prophylaxis  is  used  we  will  not  be  successful  in  our  efforts  at  prophylaxis  in 
most  localities,  and  therefore  this  method  should  never  be  neglected. 

2.  Destruction  of  Mosquitoes. — One  of  the  most  valuable  prophylactic 
measures  we  possess  against  malaria  is  the  destruction  of  the  insect  which 
transmits  the  disease,  i.e.,  the  mosquito,  and  in  suitable  localities  this  measure 
may  in  itself  be  sufficient  to  rid  the  locality  of  malarial  infection.  Generally, 
however,  it  will  be  found  that  it  is  practically  impossible  to  entirely  rid  a  locality 
of  mosquitoes,  and  while  we  should  do  our  utmost  in  this  direction,  we  will  have 
to  depend  also  upon  other  prophylactic  measures  if  we  expect  to  achieve  success 
in  our  endeavors.  Only  to  one  who  has  attempted  it  can  the  almost  hopeless 
task  of  exterminating  mosquitoes  in  many  regions,  especially  in  the  tropics,  be 
appreciated,  and  in  many  localities  it  is  impossible  of  accomplishment.  This 
being  so,  it  is  evidently  useless  to  expect  to  rid  a  locality  of  malaria  from 
which  the  mosquitoes  cannot  be  eliminated,  unless  the  infection  is  first 
stopped  among  the  inhabitants;  and  it  appears  to  me  that  the  greatest  hope  of 
success  in  combating  malaria  in  such  localities  lies  in  the  distribution  of  quinine 
to  the  inhabitants.  On  the  other  hand,  it  has  been  proven  in  a  few  instances  that 
the  destruction  of  the  mosquito  alone  was  sufficient  to  cause  a  practical  disap- 
pearance of  malaria. 


1901 

1902 

1903 

1904 

i9°S 

1990 

1548 

214 

9° 

37 

348       DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 

The  success  of  mosquito  extermination  depends  entirely  upon  local  con- 
ditions as  regards  terrain,  the  size  of  the  infected  territory,  and  climatic  changes. 

As  examples  of  the  success  attending  the  destruction  of  mosquitoes  in  the 
prophylaxis  of  malaria  may  be  mentioned  the  following: 

At  Ismailia,  a  town  of  6000  inhabitants,  upon  the  Suez  Canal,  the  pro- 
phylaxis of  malaria  was  undertaken  in  1902,  by  the  destruction  of  mosquitoes. 
In  1900  there  had  been  over  2,000  cases  of  malaria  in  Ismailia  and  the  results 
attending  mosquito  destruction  are  seen  from  the  following  figures: 

Years,  1900 

Cases,  2250 

At  the  beginning  of  1906  Ismailia  was  declared  to  be  free  from  malarial 
infection,  and  Pressat,  who  has  reported  these  results,  claims  that  he  was  able  to 
effect  the  greater  part  of  the  work,  as  regards  destruction  of  the  mosquitoes,  by 
a  mosquito  brigade  of  only  four  men.  Quinine  prophylaxia  was  used  also  at 
Ismailia. 

The  effects  of  mosquito  destruction  upon  malaria  is  brilliantly  illustrated 
by  the  campaign  against  these  insects  carried  on  at  Klang  and  Port  Swettenham, 
in  the  Federated  Malay  States,  by  Watson  and  Travers,  and  reported  by  them 
and  by  Ronald  Ross.  The  following  figures  show  the  diminution  in  malaria 
after  mosquito  prophylaxis  was  instituted. 

Years, 
Cases, 

The  mosquito  campaign  was  commenced  in  1902. 

The  results  achieved  by  Col.  Gorgas,  of  the  U.  S.  Army,  in  exterminating 
the  mosquitoes  of  Havana  will  always  stand  as  a  monument  to  the  efficiency  of 
this  method  of  prophylaxis  against  yellow  fever  and  malaria,  as  is  shown  by  the 
following  figures,  the  mosquito  campaign  commencing  in  1900: 

Years,  1895     1896     1987     1898     1899     1900     1901     1902     1903 

YellowFever,  552     1385       745       128       122       302  500 

Malaria,  206       450       811     1907       909       325       151         77         51 

The  results  secured  upon  the  Isthmus  of  Panama  will  be  discussed  later. 

Mosquitoes  may  be  destroyed  in  the  larval  and  the  adult  stage,  and  by 
chemical,  physical,  and  biological  methods. 

tj(  Chemical  methods  are  efficient  in  all  stages  of  development  of  the  insect, 
and  many  substances  have  been  experimented  with  in  the  hope  of  obtaining  one 
which  would  prove  efficacious,  being  at  the  same  time  cheap  and  easily  obtained. 
Howard,  in  1892,  published  the  result  of  his  work  upon  the  destruction  of 
mosquito  larvae  by  sprinkling  a  thin  layer  of  kerosene  upon  the  surface  of  the 
water  in  which  they  breed.  This  method  acts  mechanically  by  preventing  the 
larvae  from  reaching  the  air  when  they  attempt  to  breathe,  but  it  also  is  capable 
of  killing  the  adult  mosquito  when  in  the  act  of  depositing  her  eggs.     It  is 


1901 

1902 

1903 

1904 

^05 

610 

199 

69 

32 

23 

DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       349 

especially  applicable  to  collections  of  water  which  cannot  be  drained  and  which 
are  not  of  great  extent.  The  quantity  of  kerosene  used  is  approximately  one 
ounce  (30  gms.)  to  every  15  square  feet  of  surface,  but  enough  should  be  used  to 
entirely  cover  the  surface  of  the  water.  The  application  does  not  need  to  be 
renewed  more  than  once  a  month  in  most  instances,  although  I  believe  that  it 
would  be  better  to  renew  the  application  at  least  every  three  weeks.  This 
method  has  been  very  extensively  used  in  all  parts  of  the  words  with  very  great 
success,  and  it  is  invaluable  in  rendering  artificial  collections  of  water  harmless, 
as  well  as  water  in  fire  buckets  and  other  receptacles  which  would  prove  to  be 
breeding  places  for  mosquitoes. 

Many  other  chemical  substances  are  capable  of  killing  the  larvae,  such  as 
sulphurous  oxide,  permanganate  of  potassium,  hydrochloric  acid,  sulphate  of 
iron  or  copper,  corrosive  sublimate,  formalin,  cresol,  certain  aniline  dyes,  and  coal 
tar.  Celli  has  experimented  very  extensively  with  various  chemical  agents  and 
has  found  that  larvicide  and  gallol,  two  aniline  dyes,  are  very  efficient,  the  first 
killing  the  larvae  in  24  hours  if  added  to  the  water  in  the  proportion  of  0.00015 
parts  per  mille,  the  second  in  the  same  time  in  the  proportion  of  0.0125  parts  per 
mille.  These  dyes  are  not  poisonous  to  man  or  to  animals,  and  if  added  to  the 
water  in  larger  amount  will  kill  the  larvae  in  twelve  hours.  He  believes  that 
these  substances  are  superior  to  kerosene  and  that  they  deserve  a  more  extended 
use. 

The  powder  of  the  unexpanded  flowers  of  the  chrysanthemum,  or  pyreth- 
rum  powder,  is  a  very  efficient  larvicidal  substance  and  is  easily  soluble  in 
water. 

Of  all  the  chemical  agents  mentioned  the  only  ones  of  practical  interest 
are  pyrethrum  powder,  the  aniline  dyes,  larvicide  and  gallol,  and  petroleum. 
Of  these  the  most  widely  used  has  been  petroleum  and  it  is  also  the  cheapest  and 
probably  the  most  generally  practical,  although  I  believe  that  the  aniline  dyes 
should  be  given  a  more  extended  trial.  It  is  of  great  importance  to  inspect  the 
pools  which  have  been  treated  with  petroleum  at  least  every  week,  and  see  that 
the  film  of  oil  remains  constant,  as  it  is  very  apt  to  become  displaced  by  currents 
created  by  winds  and  by  the  movements  of  aquatic  animals.  It  will  not  in- 
frequently be  found  impossible,  in  tropical  regions  especially,  to  make  a  very 
extended  use  of  petroleum  in  the  destruction  of  mosquito  larvae,  and  in  such 
regions,  because  of  the  luxuriant  jungle  growth,  it  is  often  impossible  to  even 
locate  the  breeding-places  of  the  mosquitoes  which  abound.  The  experience  of 
James,  at  Mian  Mir,  in  India,  where  despite  the  most  careful  oiling  and  drain- 
age, the  Anopheles  still  continued  to  breed,  is  an  example  of  the  ill  success  which 
will  attend  our  efforts  in  not  a  few  localities. 

The  destruction  of  the  adult  mosquito  is  possible  by  means  of  many 
chemical  substances,  such  as  the  fumes  of  burning  pyrethrum  powder,  tobacco 
smoke,  sulphur  dioxide,  eucalyptus,  larvicide,  and  pitch,  or  by  odors  such  as 
those  from  the  essential  oil  of  turpentine,  camphor,  musk,  menthol,  and  nutmeg. 
These  substances  are  many  of  them  useful  in  houses  at  night,  being  burned  or 


350       DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 

exposed  when  the  mosquitoes  begin  to  appear.  Thus  pyrethrum  powder  or 
tobacco  may  be  burned  early  in  the  evening  in  the  living-rooms  and  bed-rooms 
and  thus  the  insects  present  many  be  destroyed  and  many  prevented  from 
entering  by  the  odor  of  these  substances.  The  most  powerful  of  the  fumes  are 
those  from  tobacco,  which  kill  mosquitoes  instantly,  while  pyrethrum  powder 
produces  death  in  five  minutes.  Sulphur  dioxide  is  the  most  powerful  of  the 
gases,  producing  death  instantly,  and  is  easily  generated  by  burning  sulphur; 
it  is  much  used  for  the  destruction  of  mosquitoes  in  the  holds  of  ships  and  in 
buildings  which  can  be  closed  tightly  and  kept  so  for  a  sufficient  period  to  allow 
thorough  disinfection  as  regards  mosquitoes.  This  agent  is  not  a  suitable  one 
for  household  use  because  of  the  irritating  character  of  the  gas.  Celli  has  ex- 
perimented, in  company  with  Casigrandi,  upon  a  large  number  of  chemical 
substances  which  may  be  used  in  the  destruction  of  the  adult  mosquito,  and  the 
following  table  is  compiled  from  their  report. 

Action  of  Culicidal  Substances  on  Adult  Mosquitoes  of  the  Genus 

Anopheles. 


Substances  used 


Time  in  .which  death  occurred 


Apparent 


Real 


I.   Gases. 

Sulphur  dioxide      

Hydrogen  sulphide     

Ammonia     

Illuminating  gas     

Formaldehyde 

77.   Fumes. 

Of  tobacco 

Of  larvicide      

Of  pyrethrum  powder 

Of  valerian  root 

Of  fresh  leaves  of  eucalyptus 

III.  Odors. 

Of  oil  of  turpentine 

Of  iodoform     

Of  menthol    

Of  nutmeg 

Of  musk 

Of  camphor 


Instantly 
Instantly 

i  m. 

i  m. 

2  m. 

Instantly 
Instantly 

5  m. 

5  m. 
3  m.-s  m. 

i  m. 
io  m. 
io  m. 
io  m. 


o  m. 


4  m.-s  m. 


i  m. 
i  m. 

2  m. 

2  m. 

io  m.-i  5  m. 

i  m.— 3  m. 

5  m- 
i  hr. 

2  hr. 

3  hr- 

i  m. 
40  m. 

4  5  m- 
2  hr 
3hr. 
4  hr.— s  hi. 


The  great  objection  to  the  use  of  any  of  these  substances  is  the  fact  that 
in  order  to  be  efficient  the  air  of  the  room  has  to  be  saturated  and  only  a  few  of 
them  are  available  for  habitual  use  on  this  account,  as  most  of  them  are  too 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       35 1 

disagreeable  to  enable  one  with  any  comfort  to  remain  in  a  room  in  which  the 
air  is  saturated.  Celli  found  a  powder  composed  of  larvicide,  the  unexpanded 
flowers  of  the  chrysanthemum,  and  valerian  root  to  be  less  disagreeable  and 
more  efficient  than  any  other  chemical  substance  for  the  destruction  of  the 
adult  insect,  one  to  two  tablespoonfuls  burned  in  the  room  in  the  evening 
stupefying  the  mosquitoes  until  morning. 

The  biological  means  available  for  the  destruction  of  mosquitoes  consist 
in  the  use  of  fish  which  will  devour  the  larvae,  the  use  of  insects  which  will 
devour  the  adult  mosquito,  and  the  introduction  into  the  breeding-places  of 
vegetable  organisms  capable  of  destroying  the  larvae  and  nymphae.  All  of  these 
methods  have  been  used,  but  it  must  be  said  with  but  little  success.  The  intro- 
duction of  fish  into  certain  reservoirs  from  which  the  water  was  used  for  drinking 
purposes,  but  which  abounded  with  mosquito  larvae,  has  been  tried  with  partial 
success,  the  fish  used  being  the  German  carp  or  the  common  little  stickle-backs. 
The  rearing  of  dragon  flies,  which  destroy  the  mosquito  in  both  the  larval 
and  adult  stage,  in  ponds  filled  with  larvae,  has  been  suggested  and  tried,  but 
with  very  little  success.  Galli-Valerio  and  de  Jongh,  in  their  experiments 
upon  animals  or  plants  that  kill  or  impede  the  development  of  mosquitoes, 
found  that  Triton  cristatus  was  very  efficient  in  destroying  the  larvae,  and  that 
cultures  of  Aspergillus  niger.  and  Aspergillus  glaucus  when  added  to  water 
containing  the  larvae  quickly  destroyed  them.  They  tried  the  latter  method 
with  success  upon  natural  collections  of  water,  and  it  would  appear  that  this 
method  merits  attention  and  experiment. 

The  physical  means  available  for  the  destruction  of  mosquitoes  and  their 
larvae  consist  in  the  destruction  of  the  breeding-places  by  drainiage,  filling 
in  of  low  land,  and  removal  of  shelter  for  the  insects.  The  most  important 
of  all  methods  of  destroying  the  mosquito  larvae  is  that  by  drainage  of  the  breed- 
ing-places, and  this  is  a  method  which  can  be  applied  over  very  large  areas  of 
country  in  which  malaria  is  endemic,  and  which  has  been  proven  to  be  of  the 
greatest  service  in  the  fight  against  these  fevers.  To  secure  results,  however, 
in  the  drainage  of  malarial  localities  we  must  have  the  support  of  the  local  and 
often  also  of  the  state  authorities,  for  this  method  of  prophylaxis  calls  for  the 
expenditure  of  large  sums  of  money  in  many  instances,  and  to  secure  them  the 
consent  of  the  state  is  essential.  In  many  regions  in  which  malaria  is  endemic 
in  its  most  virulent  form,  drainage  is  feasible  and  can  be  carried  out  with  but 
little  trouble,  although  the  expense  involved  is  often  apparently  prohibitory, 
but  as  Celli  says,  "such  methods  for  the  destruction  of  the  mosquitoes,  while 
experimentally  soluble,  will  only  be  practically  so  when  economic  interests 
demand  it."  Where  drainage  is  impossible  the  breeding-places  of  mosquitoes 
may  be  filled  in  with  sand  or  loam,  and  it  is  always  important  in  malarious 
localities  to  fill  up  all  areas  of  depression  in  the  surface  of  the  land  that  cannot 
be  adequately  drained.  Swampy  areas,  if  not  too  large,  may  thus  be  filled  in 
and  one  of  the  greatest  sources  of  mosquitoes  eliminated.  The  success  that  has 
attended  the  campaign  against  the  mosquito  upon  the  Isthmus  of  Panama  is 


352       DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARLAL  FEVERS. 

due  very  largely  to  drainage  and  the  filling  in  of  depressions  which  would  serve 
as  breeding-places  for  the  insects. 

Another  most  important  method  of  destroying  mosquitoes  is  the  removal, 
so  far  as  possible,  of  all  shelter  such  as  is  afforded  them  by  jungles,  long  grass, 
luxuriant  vegetation,  and  decaying  vegetable  matter  along  the  edges  of  streams. 
The  clearing  of  tropical  jungles  for  a  distance  of  at  least  a  mile  from  inhabited 
districts;  the  removal  of  high  grass  from  about  residences;  the  clearing  of  the 
water  of  small  streams  are  all  of  importance  in  the  prophylaxis  of  malaria.  At 
Camp  Stotsenburg,  P.  I.,  it  was  invariably  noted  that  mosquitoes  increased 
greatly  in  number  whenever  the  grass  about  the  post  was  allowed  to  grow  to 
any  length,  and  that  a  coincident  increase  occurred  in  the  number  of  malarial 
infections.  The  cutting  of  the  grass  was  followed  at  once  by  a  marked  diminu- 
tion in  the  number  of  mosquitoes  and  in  the  cases  of  malaria.  At  one  time, 
on  account  of  the  lack  of  facilities,  the  grass  was  allowed  to  grow  for  weeks  and 
the  mosquitoes  became  so  numerous  as  to  be  almost  unbearable  while  the 
number  of  cases  of  malaria  admitted  to  the  hospital  became  alarming.  The 
change  brought  about  by  the  mowing  of  the  grass  was  remarkable  and  proved 
conclusively  the  great  danger  of  affording  shelter  to  the  mosquito. 

Besides  the  methods  mentioned  the  formation  of  mosquito  brigades,  as 
suggested  by  Ross,  is  of  the  greatest  service  in  limiting  malarial  infection. 
The  brigades  consist  of  a  certain  number  of  men,  the  number  varying  with  the 
ground  to  be  covered,  whose  business  it  is  to  inspect  the  premises  of  every 
individual  in  a  locality  and  destroy  the  larvae  in  the  small  breeding-places 
which  harbor  the  Anopheles,  such  as  domestic  water  receptacles,  water  butts, 
and  tanks;  the  removal  of  small  puddles  in  streets  and  yards  as  well  as  empty 
tins,  jars,  broken  bottles,  or  anything  in  which  water  may  collect  and  in  which 
mosquitoes  may  breed.  In  the  formation  of  such  brigades  the  area  to  be  covered 
such  as  a  town  or  city,  is  divided  into  districts,  to  each  district  being  assigned  an 
overseer  and  a  number  of  men,  whose  entire  time  is  occupied  in  searching  for, 
and  destroying  the  breeding-places  of  mosquitoes.  Methods  similar  to  this 
were  employed  in  Havana  by  Colonel  Gorgas,  and  resulted  in  the  almost 
total  disappearance  of  the  yellow  fever  mosquito  from  that  city. 

Garden  wells  and  water  barrels  and  tanks,  being  prolific  sources  of  mosqui- 
toes, should  be  covered  with  wire  netting,  thus  preventing  the  laying  of  the  eggs 
and  the  development  of  the  larvae.  If  this  is  not  practicable  the  surface  of  the 
water,  if  not  used  for  drinking  purposes,  should  be  covered  with  petroleum. 

The  results  obtained  by  Colonel  Gorgas,  of  the  Medical  Corps  of  the  U.  S. 
Army,  in  the  prevention  of  yellow  fever  and  malaria  upon  the  Isthmus  of 
Panama  by  the  use  of  the  physical  methods  of  destroying  mosquitoes  just 
mentioned,  prove  conclusively  the  value  of  such  methods  in  the  prophylaxis 
of  malaria.  As  is  well  known,  the  Isthmus  of  Panama  has  for  centuries  been 
notorious  for  the  prevalence  of  yellow  fever  and  the  most  pernicious  forms  of 
malaria,  and  during  the  days  of  the  French  control  of  the  Isthmian  canal, 
work  was  rendered  difficult,  and  many  times  impossible,  by  reason  of  the  great 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       353 

mortality  of  the  laborers  employed  in  digging  the  canal.  How  different  has  been 
the  history  of  the  American  "occupation"  of  the  Isthmus  of  Panama.  To-day 
the  canal  is  being  built,  and  it  is  being  built  with  a  smaller  sick  rate  than  the 
normal  one  of  many  European  and  American  cities,  and  this  great  difference 
is  due  entirely  to  the  destruction  of  mosquitoes  and  modern  sanitation.  No 
greater  object  lesson  exists  to-day  of  the  beneficent  results  of  sanitary  science 
than  the  Panama  Canal.  The  following  data  illustrates  what  has  been 
accomplished  in  the  prevention  of  yellow  fever  and  malaria  upon  the  Isthmus 
of  Panama. 

As  regards  yellow  fever  the  cities  of  Panama  and  Colon,  once  hot-beds 
of  this  disease,  have  been  entirely  free  from  this  fever  for  years,  and  this  is 
true  also  of  the  Canal  Zone.  As  regards  the  malarial  fevers,  the  following 
table,  given  by  Colonel  Gorgas,  illustrates  the  decrease  in  these  fevers: 


Year. 

Force 
Employed. 

No.   Cases 
Admitted. 

No.  Cases  per 
Thousand. 

No.  Deaths. 

No.  Deaths  per 
Thousand. 

1905 
1906 
1907 
1908 

16511 
26705 
39344 
43890 

8496 
21938 
16709 

12372 

5i4 
821 
424 
282 

92 
199 
138 

59 

5-57 
7-45 
3-51 
i-34 

From  this  table  it  will  be  seen  that  despite  the  fact  that  the  force  employed 
upon  the  Isthmus  is  constantly  increasing  the  number  of  cases  of  malaria  is 
steadily  decreasing.  These  results  have  been  achieved  by  screening,  destroy- 
ing the  breeding  places  of  mosquitoes,  the  prophylactic  use  of  quinine,  and 
oiling  where  drainage  was  impracticable. 

3.  Protection  of  Man  from  the  Bites  of  Mosquitoes. — One  of  the 
most  valuable  methods  of  malarial  prophylaxis  is  the  protection  of  individuals 
from  the  bites  of  Anopheles.  This  protection  applies  not  only  to  uninfected 
persons,  but  is  especially  important  in  the  case  of  those  suffering  from  these 
fevers.  Such  protection  may  be  secured  by  the  use  of  screening  about  houses, 
head  nets,  mosquito  bars,  certain  substances  placed  upon  the  skin,  the  isola- 
tion of  patients  suffering  from  malaria,  and,  of  course,  by  the  methods  of 
mosquito  destruction  which  I  have  already  described. 

Isolation  of  Malarial  Patients  in  screened  rooms  is  of  the  greatest 
importance  from  a  prophylactic  standpoint,  and  yet  how  seldom  we  see  this 
precaution  taken  even  in  regions  in  which  the  malarial  fevers  are  endemic  and 
severe.  We  have  seen  that  the  mosquito  is  necessary  as  an  intermediate  host 
in  the  life  history  of  the  malarial  plasmodia  and  that  the  mosquito  becomes 
infected  by  biting  an  individual  suffering  from  malarial  disease.  From  this 
it  is  obvious  that  if  we  can  place  the  infected  individual  in  a  position  where  the 
mosquitoes  cannot  gain  access  to  him  the  transmission  of  the  infection  will 
23 


354       DIAGNOSIS,   PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 

be  impossible.  Theoretically,  if  every  individual  infected  with  malaria  could 
be  screened  from  mosquitoes  for  a  sufficient  period  of  time  these  fevers  would 
disappear,  but  practically  the  infection  is  of  such  a  nature  that  even  when  no 
symptoms  are  present  the  plasmodia  may  be  present  in  the  blood  and  thus  the 
mosquitoes  may  become  infected.  In  aestivo-autumnal  infections  the  cres- 
centic  form  of  the  plasmodia  (gamete),  the  very  form  intended  to  undergo  its 
life  cycle  in  the  mosquito  is  very  frequently  present  in  the  blood  when  no 
symptoms  of  malaria  are  noticeable,  so  that  it  is  obvious  that  we  cannot  in  this 
way  entirely  prevent  malaria,  but  in  the  light  of  our  present  knowledge  the 
malarial  fevers  should  be  regarded  as  infectious  and  the  patient  strictly  isolated 
in  a  screened  room,  and  he  who  neglects  to  thus  protect  the  uninfected  is  guilty 
of  gross  negligence.  Not  only  is  this  isolation  of  importance  to  those  surround- 
ing the  patient,  but  also  to  himself,  for  if  he  his  not  protected  from  mosquitoes 
he  is  constantly  exposed  to  reinfection  by  the  bites  of  these  insects.  This  form 
of  prophylaxis  should  never  be  neglected  in  any  locality,  but  is  especially 
important  in  regions  were  the  pernicious  forms  of  malaria  are  prevalent. 

In  addition  to  isolation  of  the  malarial  patient,  segregation  of  the  natives 
in  tropical  regions  has  been  suggested  by  Ross  and  Stephens  as  a  measure  of 
great  value  in  the  prevention  of  malarial  infection  among  the  foreign  European 
population.  I  have  already  shown  how  frequent  is  latent  malarial  infection 
in  natives  of  malarial  localities  and  how  often  the  disease  is  masked  by  other 
symptoms.  By  segregation  of  the  natives  we  at  once  remove  a  common  source 
of  infection  in  the  person  of  the  natives  suffering  from  a  latent  infection,  and 
also  protect  the  European  from  the  effects  of  the  filthy  habits  of  the  native 
population.  The  suggestion  of  Ross  and  Stephens  that  the  European  quarter 
should  not  be  placed,  as  is  common,  in  the  midst  of  the  native  village  or  city  in 
malarious  localities,  but  should  be  situated  at  some  distance,  is  an  excellent 
one,  for  it  is  often  impossible  to  secure  proper  hygienic  conditions  if  we  be  forced 
to  live  among  a  native  population.  Unfortunately,  for  business  reasons,  it 
is  generally  impossible  to  do  much  in  the  way  of  segregation  of  the  native, 
although  the  method  is  applicable  in  the  establishment  of  military  posts  and 
camps. 

The  screening  of  all  dwelling-houses  in  malarial  regions  is  a  measure 
which  has  resulted  in  infinite  good  as  regards  the  prophylaxis  of  malaria, 
and  one  that  should  be  insisted  upon  by  every  sanitarian.  The  screening  used 
should  be  of  copper  wire  if  possible,  containing  n  wires  to  2  cm.  of  surface. 
The  use  of  wire  screening  other  than  copper  is  more  expensive  in  the  end,  as 
such  screening  quickly  rusts  and  becomes  useless.  If  other  screens  be  used 
the  netting  should  be  covered  with  two  coats  of  good  paint.  The  experiments 
of  Sambon  and  Low,  repeated  by  many  others,  prove  conclusively  that  even  in 
the  most  malarious  regions  the  infection  may  be  escaped  by  living  in  properly 
screened  houses.  Sbacchi  has  shown  that,  in  the  case  of  the  employee's  of  the 
Sicula  Occidentale  Railway  in  Italy,  those  protected  by  living  in  mosquito-proof 
houses  suffered  but  little  from  malaria,  while  those  not  so  protected  developed 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       355 

the  disease  in  almost  every  case.  Of  641  persons  living  in  screened  habitations, 
only  4.8  per  cent,  developed  malaria,  which  corresponds  to  the  results  obtained 
by  quinine  prophylaxis,  and  it  is  probable  that  had  both  methods  been  used  the 
malarial  percentage  would  have  been  almost  nil.  The  barracks  of  troops 
serving  in  malarial  localities  should  be  carefully  screened,  for  this  will  not  only 
protect  them  from  malaria,  but  also  from  yellow  fever  and  dengue.  The 
latter  disease  has  been  proved  by  Graham  and  Ashburn  and  myself  to  be 
transmitted  by  Culex  fatigans ,  and  our  work  has  been  confirmed  by  Phelan  and 
Nichols,  so  that  screening  of  the  barracks  of  troops  or  dwelling-houses  in  infected 
localities  offers  a  large  measure  of  protection  against  the  malarial  fevers,  yellow 
fever,  dengue,  and  filiariasis.  Probably  no  one  sanitary  measure  which  can  be 
accomplished  at  so  little  cost  is  productive  of  so  much  good  and  protects 
against  so  many  diseases  as  does  the  screening  of  buildings  against  mosquitoes. 

In  conjunction  with  the  screening  of  houses  and  barracks  the  use  of  the 
mosquito  bar  for  the  bed,  and  the  head  net  and  gloves  for  wear  when  obliged 
to  be  out  at  night,  are  very  valuable  prophylactic  measures.  In  houses  or 
barracks  which  are  not  screened,  the  use  of  the  mosquito  bar  for  the  bed  should 
never  be  neglected,  and  it  is  also  well  to  provide  a  small  mosquito-proof  com- 
partment, either  in  a  room  or  upon  the  porch,  for  use  in  the  late  afternoon  and 
evening.  The  use  of  the  mosquito  bar  has  very  greatly  reduced  the  number  of 
cases  of  malaria  in  our  posts  in  the  Philippines  and  Cuba,  but  strict  attention 
must  be  paid  to  the  enforcement  of  the  use  of  this  bar  in  military  commands,  as 
the  soldier  generally  dislikes  to  sleep  under  it  on  account  of  the  heat.  An 
inspection  of  the  barracks  at  night  after  the  men  have  retired  will  generally 
demonstrate  that  many  of  the  men  are  not  using  the  bar  or  that  it  is  improperly 
used,  and  such  inspections  are  necessary  if  we  are  to  secure  good  results  from 
this  method  of  prophylaxis.  When  mosquito  bars  are  used  they  should  be 
large  enough  to  be  suspended  several  feet  above  the  bed,  and  should  be  placed 
in  position  and  tucked  beneath  the  mattress  early  in  the  evening,  and  examined 
before  retiring  in  order  to  see  that  mosquitoes  have  not  gained  an  entrance. 
The  mosquito  bar  for  protection  of  the  bed  is  an  absolute  necessity  in  malarial 
regions,  and  should  always  be  carried  by  the  traveler  in  such  regions.  To 
neglect  its  use  is  to  invite  infection. 

By  the  use  of  the  methods  mentioned  for  the  protection  of  man  from  the 
bites  of  the  Anophelinae,  especially  by  the  screening  of  barracks,  Procaccini,  in 
Sardinia,  reduced  the  number  of  cases  of  malaria  among  the  troops  from  70 
per  cent,  to  57  per  cent.,  in  one  season,  and  later  the  percentage  was  reduced 
to  less  than  20  per  cent.  In  Formosa,  Tzuzuki  protected  115  soldiers  by 
screening  their  barracks  from  Sept.  2 1  to  Dec.  8,  and  not  a  case  of  malaria  de- 
veloped, while  in  the  same  time  among  717  soldiers  not  so  protected  there  devel- 
oped 251  malarial  infections.  Head  nets  were  used  during  the  day  and  the 
men  were  confined  to  the  barracks  after  dark. 

This  experiment  of  Tzuzuki's  shows  what  may  be  accomplished  by  a 
rigid  enforcement  of  the  use  of  screens  in  the  prophylaxis  of  malaria,  but  it 


356       DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 

is  doubtful  if  our  soldiers  would  consent  to  being  confined  to  their  barracks 
as  did  the  Japanese.  Nevertheless,  great  good  may  be  accomplished  by  as 
rigid  an  enforcement  as  possible  of  the  use  of  the  mosquito  bar,  and  in  the 
tropics  and  in  all  malarial  localities  our  military  barracks  should  be  thoroughly 
screened. 

The  use  of  punkas  and  of  electric  fans  is  of  service  in  keeping  mosquitoes 
away  by  keeping  the  air  in  motion,  while  the  burning  of  pyrethrum  powder  or 
larvicide  is  efficient  in  small  rooms,  stupefying  the  insects  so  that  they  are 
unable  to  bite.  Everyone  who  has  lived  in  malarial  regions  is  aware  of  the 
protection  afforded  one  when  smoking  a  cigar  or  pipe,  a  protection  which 
really  constitutes  the  strongest  argument  for  the  use  of  tobacco  in  the  tropics. 

A  limited  amount  of  protection  is  afforded  against  mosquito  bites  by  ap- 
plications to  the  skin  of  such  substances  as  oil  of  citronella,  oil  of  eucalyptus, 
camphor,  and  petroleum,  or  covering  the  skin  with  bland  ointments,  which 
prevent  the  mosquito  from  biting  by  reason  of  mechanical  interference.  Mense 
recommends  a  solution  of  quinine  and  glycerine,  i-iooo  rubbed  upon  the  skin, 
as  an  efficient  protective.  All  of  these  substances  are  more  or  less  unpleasant 
and  the  protection  afforded  is  evanescent,  so  that  they  are  really  of  but  little 
practical  value  in  the  prophylaxis  of  malaria. 

4.  Education  of  the  Public  Regarding  Malarial  Prophylaxis. — As  so 
many  of  our  best  methods  of  prophylaxis  against  malaria  are  dependent  upon 
the  public  support,  because  of  their  financial  and  social  aspects,  it  is  essential 
that  for  their  success,  the  public  be  informed  as  to  their  nature  and  what  is 
expected  to  be  accomplished  by  their  use.  In  Italy  this  has  been  accomplished 
by  the  Society  for  the  Study  of  Malaria  to  such  an  extent  that  there  is  probably 
no  one  so  ignorant  in  that  country  as  to  doubt  the  efficiency  of  the  methods 
already  instituted  for  the  suppression  of  malaria,  or  who  does  not  know  why 
they  were  instituted,  and  how  they  are  proving  successful.  The  example  of 
Italy  may  well  be  followed  by  every  state  in  which  malaria  is  endemic,  for  only 
by  educating  the  public  can  we  hope  to  fight  a  winning  battle  against  these 
infections.  Thus  the  education  of  the  public  is  a  powerful  means  of  prophylaxis 
against  malaria,  for  upon  the  response  of  the  public,  both  financially  and 
socially,  must  we  depend  for  the  sinews  of  war. 

Besides  the  more  important  prophylactic  measures  which  have  been 
mentioned,  there  are  certain  measures  which  may  be  taken  by  the  individual 
which  will  assist  in  protecting  him  from  malaria.  Fatigue,  exposure  to  rain  and 
to  the  sun,  excessive  indulgence  in  alcoholics,  and  excesses  of  every  kind  should 
be  avoided  in  malarial  regions,  for  these  all  deplete  the  natural  resisting  powers 
of  the  individual  and  render  him  more  liable  to  infection.  In  traveling,  the 
season  of  the  year  in  which  the  malarial  fevers  are  most  prevalent  should  not  be 
selected,  if  possible,  and  the  journeys  should  be  made  in  the  daytime.  In  the 
selection  of  camp  sites  and  sites  for  building,  high,  well-drained  land  should  be 
chosen,  and  the  vicinity  of  swamps  and  collections  of  water  carefully  avoided. 
The  drinking-water  should  always  be  boiled,  for,  while  malaria  is  not  transmitted 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       357 

by  water,  this  measure  may  prevent  other  diseases  which  would  so  weaken  the 
individual  as  to  render  him  an  easy  prey  to  infection.  The  prophylactic  use  of 
quinine  and  the  use  of  a  mosquito  net  at  night  should  never  be  neglected  by  the 
traveler  in  malarial  regions. 

General  Summary. — The  methods  which  have  been  found  serviceable  in 
the  prophylaxis  of  malaria  may  be  briefly  summarized  as  follows: 

1.  The  prophylactic  use  of  quinine,  in  daily  doses  of  from  0.12  to  0.30  gm. 
(2  to  5  grains),  according  to  the  severity  of  the  malarial  infection  in  the  locality 
in  which  this  method  of  prophylaxis  is  practiced.  The  administration  of 
quinine  to  all  natives,  both  infected  and  uninfected,  is  a  most  valuable  measure, 
but  requires  governmental  control,  which,  in  many  places,  we  are  unable  to 
secure. 

2.  The  destruction  of  the  breeding-places  of  mosquitoes  by  drainage  and 
filling  in,  and  the  destruction  of  the  insects  by  other  methods  which  have  been 
described. 

3.  Protection  of  man  from  the  bite  of  mosquitoes,  secured  by  screening  all 
buildings  in  which  he  lives  or  works;  the  use  of  mosquito  bars;  head  nets,  and 
gloves;  and  of  various  fumes  and  applications  to  the  skin. 

4.  The  avoidance  of  all  excesses  and  of  exposure  of  the  person  to  rains, 
the  tropical  sun,  and  to  physical  hardships. 

5.  The  education  of  the  public  to  the  importance  of  the  prevention  of  the 
malarial  fevers. 

6.  The  segregation  of  the  natives  in  malarial  regions;  a  simple  and  very 
efficient  measure,  but  one  that  can  be  carried  out  only  in  rare  instances  because 
of  political,  business,  and  social  reasons. 

The  method  of  prophylaxis  suggested  by  Kuhn,  which  consists  in  produc- 
ing immunity  to  malaria  by  the  injection  of  horse  serum  from  horses  immunized 
to  "horse  pest"  is,  at  the  present  time,  of  no  practical  importance.  While  he 
claims  that  the  injection  of  such  serum  kills  the  plasmodia  and  produces  im- 
munity, his  results  have  not  been  confirmed,  and  it  is  very  problematical  if  they 
will  be  in  the  future. 

The  Existence  of  the  Plasmodia  Outside  Man  and  the  Mosquito. — As 
to  whether  the  plasmodia  of  malaria  may  exist  in  any  form  outside  of  man  and 
the  mosquito  our  knowledge  is  very  limited,  but  such  as  it  is  it  would  appear  to 
prove  that  the  parasites  cannot  so  exist.  Schaudinn  has  demonstrated  that  the 
sporozoites  are  very  delicate,  degenerating  when  placed  in  water,  or  in  blood 
serum  removed  from  the  human  body,  and  his  experiments  would  appear  to 
prove  that  malaria  cannot  be  transmitted  by  water  containing  mosquitoes 
infected  with  the  malarial  plasmodia.  More  work  should  be  done  along  this 
line,  however,  before  we  can  be  sure  that  malaria  is  not  transmitted  save  by  the 
mosquito. 

So  far  as  we  know,  the  plasmodia  of  malaria  do  not  occur  in  any  of  the 
lower  animals,  although  plasmodia  have  been  found  in  bats  and  monkeys  which 
very  closely  resemble  the  human  parasites  in  morphology.     Dionisi  has  de- 


358       DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 

scribed  three  species  occurring  in  bats,  but  they  may  be  easily  differentiated 
from  those  occurring  in  man.  Koch  found  a  plasmodium  in  monkeys  which 
resembles  somewhat  Plasm  odium  vivax  of  man,  but  this  organism  could  not  be 
transmitted  to  man  nor  could  human  malaria  be  transmitted  to  monkeys. 
Richard,  Di  Mattei,  Fischer,  and  Koch  have  all  endeavored  to  transmit  the 
malaria  of  man  to  monkeys,  but  without  success.  Koch  has  demonstrated  that 
it  is  impossible  even  in  the  case  of  the  anthropomorphic  apes;  he  experimented 
upon  three  orang-outangs  and  three  Hylobatcs  agilis,  injecting  both  the  blood  of 
patients  suffering  from  tertian  and  from  aestivo-autumnal  malaria,  but  without 
being  able  to  produce  the  slightest  symptom  of  infection,  while  the  blood  of 
these  animals  remained  free  of  the  plasmodia.  It  would  appear,  therefore, 
that  the  conclusion  is  justified  that  the  plasmodia  of  human  malaria  are  found 
only  in  the  blood  of  man  and  in  mosquitoes  belonging  to  the  Anophelinae.  The 
success  attending  the  methods  of  prophylaxis  which  have  been  described  is 
additional  proof  that  in  our  fight  against  malaria  we  have  only  to  deal  with  man 
and  the  mosquito. 

Literature  upon  the  Prophylaxis  of  the  Malarial  Fevers. 

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1899.  Buchanan,  W.J.  The  Value  of  Prophylactic  Issues  of  Cinchona  Prepa- 
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1900.      Grassi.      Erster  summarischer  Bericht  iiber  die  Versuche  zur  Verhutung 

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Tropenhyg  ,   Bd.  iv,  p.   339. 

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1902'  Gorgas,  W.  C.  Mosquito  Work  in  Havana.  Medical  Record,  vol.  xix, 
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1902.  Tzuzuki.  Ueber  die  Verwendbarkeit  des  Moskito-Drahtgazeschutzes 
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1903.  Celli.  Zur  Prophylaxe  der  Malaria.  Hyg.  Rundschau,  No.  20,  p. 
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Abst.,  Bd.  xxviii,  p.  696. 
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1903.      Frosch,   P.      Die   Malariabekampfung  in    Brioni    (Istrien).      Zeitschr.   f. 

Hyg.,  Bd.  vliii,  Heft  1. 
1903.      Gosio,  B.      Die  Behampfung  der  Malaria  der  Toscano.     Zeitschr.  f.  Hyg., 

Bd.  xliii,  Heft  1. 
1903.      Ollwig.       Die  Bekampfung  der  Malaria.      Zeitschr.  f.   Hyg.,    Bd.    vliii, 

Heft  1. 
1903.      Stephens  and  Christophers.      Report  to  the  Malarial  Commit.  Royal 

Soc,  8th  Series. 

1903.  Vagedes.  Die  Malaria  unserer  Kolonieen  im  Lichte  der  Kochschen 
Forschung.  a.  d.  Festschrift  zum  sechzigsten  Geburtstage  von  Robert 
Koch. 

1904.  James.      Report  of  the  Malarial  Committe  of  Royal  Society,  Series  8. 
1904.     James.     The   Causation   and   Prevention   of   Malarial  Fevers.     Lancet, 

Jan.  30,  p.  307. 
1904.      Editorial.      The    Success    of    Mosquito    Destruction    Operations.     Brit. 

Med.  Jour.,  No.  2281,  p.  631. 
1904.      Schaudinn,    F.      Die    Malaria   in   dem    Dorfe    "St.    Michele    de    Leuse" 

in   Istrien,  etc.,   Arc.    a.  d.  Kaiserl.   Gesundheitsamte,    Bd.   xxi,    Heft   3. 
1904.      Ed.    Sergent    and    Et.   Sergent.    Versuch   einer    Malariabekampfung. 

Annales  de  l'lnstitut.  Pasteur,  Feb.  Referat. 
1904.      Idem.      Campagne   antipaludique   en  Algerie  (1903).      Annalea  de  l'ln- 
stitut. Pasteur,  vol.  xviii,  p.  64. 
1904.      Stephens,  J.  W.      The  Antimalarial  Operations  at   Mian-Mir.      Lancet, 

vol.  clxvi,  p.  637. 
1904.     Idem.     The  Prophylaxis  of  Malaria.     Lancet,  vol.  clxvi,  p.  611. 
1904.      Zieman,  H.    Ueber  Chininprophylaxe  in  Kamerun.    Archiv.  f.  Schiffs- u. 

Tropenhyg.,  Bd.  viii,  p.  329. 
1906.      Zieman,    H.       Malaria.      Handbuch     der      Tropenkrankheiten,     Mense. 

Leipzig. 
1906.      Brignone,    G.,    and   Algona,    V.     Prophylactic   Use  of    Quinine.      Atti 

della  Soc.  per  gli  Studi  della  Malaria. 
1906.      Bettinetti.     Prophylactic  Use  of  Quinine.     Ibid. 
1906.      Celli.      Prophylactic  Use  of  Quinine.     Ibid. 
1906.      Sbacchi.      Prophylaxis  by  Wire  Gauze.      Ibid. 

1906.  Galli-Valerio  and  de  Jongh.      Life  History  of  Mosquitoes.     Ibid. 

1907.  Craig,  C.  F.  The  Malarial  Fevers.  Osier's  Modern  Medicine,  vol.  1, 
Philadelphia. 

1908.  Ross,  R.  The  Prevention  of  Malaria  in  British  Possessions,  Egypt, 
and  Parts  of  America.  Jour.  Royal  Army.  Med.  Corps,  vol.  x,  No.  2,  p. 
i55- 


CHAPTER  IV. 

The  Treatment  of  the   Malarial  Fevers. 

For  the  treatment  of  the  malarial  fevers  medicine  possesses  one  of  its 
few  true  specifics,  i.e.,  quinine,  and  by  quinine  is  meant  all  of  the  derivatives 
of  cinchona  bark.  This  bark  was  introduced  into  Europe  in  1640  by  the 
Countess  del  Cinchon,  who  had  been  treated  with  it  in  South  America,  where 
it  had  been  used  for  many  years  in  the  treatment  of  malarial  fevers  by  the 
natives.  In  1820,  Pelletier  and  Caventou  discovered  the  alkaloids  quinine 
and  cinchonine  in  the  bark,  and  in  1852,  quinidine  was  isolated.  When 
properly  administered  quinine  will  invariably  destroy  the  malarial  plasmodia, 
and  Osier  has  well  said  that  "the  physician  who  at  this  day  cannot  treat 
malarial  fever  successfully  with  quinine,  should  abandon  the  practice  of 
medicine." 

While  there  are  rare  instances  in  which  the  drug  appears  to  be  powerless 
to  limit  the  course  of  a  malarial  infection,  a  careful  study  of  such  cases  will 
invariably  show  that  it  has  been  administered  improperly.  For  instance: 
Certain  individuals  are  unable  apparently  to  absorb  quinine  through  the 
intestinal  tract,  but  in  such  indivduals  the  hypodermic  use  of  the  drug  will 
result  in  a  cure  of  the  infection.  The  successful  treatment  of  malaria  by  quinine 
depends  wholly  upon  the  proper  administration  of  the  drug. 

Historical. — The  history  of  the  discovery  of  the  efficiency  of  cinchona 
bark  in  malaria  and  its  introduction  into  Europe  is  of  much  interest  and  is  well 
told  by  Markham,  in  his  book  entitled  "A  Memoir  of  the  Lady  Ana  de  Osorio, 
Countess  of  Cinchon,"  published  in  London  in  1874.  Regarding  the  discovery 
of  the  value  of  the  drug,  Markham,  says:  "In  1638  the  Countess  of  Cinchon, 
the  wife  of  the  Viceroy  of  Peru,  lay  very  ill  with  tertian  fever  at  Lima,  the 
capitol  city.  The  news  was  carried  to  Canizares,  then  Corregidor  of  Loxa, 
a  town  among  the  Andes,  in  the  present  Ecuador.  Though  the  natives  of  Peru 
were  unacquainted  with  the  curative  power  of  the  bark,  those  of  the  more 
northern-lying  countries  appreciated  its  worth,  and  from  them  Canizares 
obtained  the  secret.  He  therefore  sent  a  parcel  of  it  to  the  vice-queen.  Her 
physician,  de  Vega,  agreed  to  its  employment,  and  she  recovered  in  a  short 
time.  In  1640  the  Countess  returned  to  Spain  and  carried  with  her  a  large 
quantity  of  the  precious  bark,  which  she  distributed  about  her  native  place  in 
the  vicinity  of  Madrid.  De  Vega  followed  and  brought  likewise  a  large  amount 
of  the  bark  to  Spain,  which  he  sold  at  Madrid  for  a  hundred  orrales  a  pound. 
The  Countess  employed  the  bark  so  extensively  that  for  a  long  time  it  bore  the 
name  'Countess's  Powder'  (Pulvis  comitissae)." 

360 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       361 

Although  the  value  of  the  bark  was  proven  beyond  doubt,  it  was  many  years 
before  it  was  used  in  general  practice.  The  bigotry  of  the  learned  of  the  day 
refused  audience  to  a  remedy  discovered  by  savages,  and  those  using  it  were 
even  subjected  to  religious  persecution.  About  the  latter  half  of  the  seventh 
century  the  bark  was  adopted  by  the  Jesuits  and  was  used  by  them  in  the  treat- 
ment of  fevers,  being  known  at  that  time  as  Jesuits'  bark,  but  "it  had  still  to 
encounter  the  sneers  of  the  learned  and  the  hate  of  bigots,  and  it  was  not  until 
an  English  quack  succeeded  in  curing  by  its  means  men  of  high  rank  that 
fashion  broke  down  the  prejudices  which  reason  could  not  remove."1 

Medicinal  Treatment. — It  is  essential  that  every  case  of  malarial  fever 
be  thoroughly  treated  with  the  specific,  quinine,  both  from  a  therapeutic  and 
prophylactic  standpoint.  The  mild  intermittent  malarial  infections,  such  as 
the  tertian  and  quartan,  tend  toward  spontaneous  recovery,  but  while  this  is 
true  in  many  instances,  it  should  be  remembered  that  even  these  infections  may 
become  malignant,  and  even  if  they  do  not,  the  occurrence  of  repeated  par- 
oxysms results  in  a  diminution  of  the  vitality  of  the  patient,  as  is  evidenced  by 
the  anaemia  which  invariably  accompanies  such  repeated  attacks.  Added  to 
this  we  have  the  important  fact  that  every  malarial  patient  is  a  source  of  infection 
to  others  unless  the  plasmodia  be  rendered  harmless,  so  that  we  must  admit 
that  every  malarial  infection,  no  matter  how  mild  in  character,  should  be 
treated  medicinally  and  not  be  left  for  nature  to  cure. 

In  considering  this  portion  of  our  subject  it  may,  for  convenience,  be 
divided  as  follows: 

1.  The  action  of  quinine  upon  the  malarial  plasmodia. 

2.  Choice  of  preparation. 

3.  Time  of  administration. 

4.  Methods  of  administration. 

5.  The  amount  to  be  administered. 

6.  Contraindications  and  substitutes. 

1.  The  Action  of  Quinine  upon  the  Malarial  Plasmodia. — That  quinine 
is  a  specific  in  the  malarial  fevers  is  proven  by  its  action  upon  the  malarial 
plasmodia.  The  drug  exerts  its  beneficial  action  upon  malarial  infections  by 
directly  destroying  the  plasmodia,  a  fact  first  proven  by  Binz  in  the  case  of 
some  other  protozoa,  and  repeatedly  confirmed  by  other  investigators  as  regards 
the  malarial  plasmodia. 

Although  a  considerable  amount  of  research  has  been  devoted  to  the 
action  of  quinine  upon  the  plasmodia  of  malaria,  reference  to  the  reports  of  the 
various  investigators  who  have  been  so  engaged  reveals  the  fact  that  much 
confusion  still  exists  regarding  the  exact  effect  of  this  drug  upon  the  plasmodia, 
and,  therefore,  the  best  time  for  its  administration  in  the  treatment  of  the 
malarial  fevers.  This  is  well  illustrated  in  the  following  quotation  from 
Manson2  who,  in  speaking  of  the  action  of  the  drug,  says: 

1  National  Dispensatory,  5th  Ed.,  p.  1352. 

2  Tropica]  Diseases,  4th  Ed.,  p.  124. 


362       DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 

"In  what  way  quinine  acts  has  not  yet  been  satisfactorily  explained.  Some, 
reasoning  from  the  toxic  influence  this  drug  exerts  on  many  kinds  of  free  amoebae, 
say  that  it  acts  in  malaria  in  the  same  way;  that  is,  as  a  direct  poison  to  the 
parasite.  They  support  this  view  by  pointing  to  the  degenerative  changes,  as 
evidenced  by  imperfect  staining  reaction,  exhibited  by  such  parasites  as  persist  in 
the  blood  after  administration  of  quinine  has  been  commenced.  Others  main- 
tain that  it  acts  in  stimulating  the  phagocytes,  the  natural  enemies  of  the  para- 
site. Some  experimentalists,  allege,  on  the  other  hand,  that  it  paralyses  the 
white  corpuscles.  •  It  is  said  by  some  to  be  most  effective  against  the  free 
spores  and  the  very  young  intracorpuscular  forms,  but  inoperative  against  the 
more  mature  parasites;  hence  they  advocate  giving  it  early  in  the  parasitic  cycle. 
Others,  on  the  contrary,  maintain  that  it  is  operative  only  on  the  large  intra- 
corpuscular forms,  and  therefore  advocate  its  use  at  a  late  stage  of  the  cycle." 

Much  confusion  which  exists  regarding  the  action  of  the  drug  upon  the 
Plasmodia  is  due,  I  believe,  to  the  staining  methods  employed  by  various 
observers,  many  of  which  were  imperfect,  and  to  the  interpretations  arrived 
at  from  them.  In  my  own  work  I  have  used  the  modified  Wright's  stain 
already  described,  by  which  method  the  chromatin  of  the  nucleus  of  the  parasite 
stains  a  brilliant  red,  the  protoplasm  a  robin's-egg  blue,  while  the  vesicular 
portion  of  the  nucleus  remains  unstained.  The  method  is  uniform  in  its  results 
and  in  the  great  number  of  specimens  examined  the  morphology  of  the  plasmodia 
after  the  administration  of  quinine  was  always  the  same  for  the  various  periods 
in  the  life  cycle  of  the  organisms. 

While  stationed  at  Camp  Stotsenburg,  P.  I.,  in  1905,  where  all  varieties  of 
the  malarial  fevers  were  prevalent,  I  spent  several  weeks  in  studying  the  effect 
of  quinine  upon  the  malarial  plasmodia,  in  order  to  determine,  if  possible,  the 
actual  effect  of  the  drug  upon  the  various  species  of  plasmodia,  and  therefore 
the  best  time  to  administer  quinine  in  treating  the  malarial  fevers.  The  conclu- 
sions arrived  at  are  the  result  of  the  examinations  of  a  very  large  number  of 
both  fresh  and  stained  specimens  of  blood  after  the  administration  of  quinine 
was  begun,  and  they  represent,  I  believe,  the  exact  action  of  the  drug  upon 
the  various  species  of  malarial  plasmodia  in  all  stages  of  their  human  life  cycle. 

Historical. — Before  considering  the  results  of  my  studies,  the  following 
historical  summary  is  of  interest:  Binz,  in  1867,  was  the  first  to  interpret  the 
curative  action  of  quinine  in  malaria  as  being  due  to  its  effect  directly  upon  the 
cause  of  the  disease,  which  he  concluded  to  be  some  low  form  of  animal  life. 
In  support  of  his  position  he  instanced  the  effect  of  solutions  of  the  drug  upon 
many  species  of  infusoria.  In  1881  Laveran  demonstrated  that  a  1-1000  solu- 
tion of  quinine  caused  the  immediate  cessation  of  the  movements  of  the  plas- 
modia when  added  to  a  preparation  of  malarial  blood  under  the  microscope  and 
asserted  that  "it  is  because  it  destroys  the  parasite  that  quinine  causes  the 
disappearance   of  the   manifestations   of  paludism." 

The  Tertian  Plasmodium. — Golgi  claimed  that  the  action  of  quinine  was 
most  marked  upon  the  tertian  Plasmodium,  even  the  adult  forms  being  affected 
by  it.  His  studies  were  made  upon  fresh  blood  and  the  changes  produced  by  the 
drug,  as  described  by  him,  consisted  in  a  shrinkage  of  the  parasites,  while  the 
protoplasm  became  coarsely  granular  and  opaque.      The  segmenting  parasites 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       363 

were  shrunken  and  contained  numerous  pigment  masses  and  a  smaller  number 
of  spores. 

Romanowsky,  using  his  admirable  staining  method,  found  that  in  the 
young  intracellular  tertian  parasites  the  drug  caused  a  disappearance  of  the 
vesicular  portion  of  the  nucleus,  while  the  chromatin  stained  less  intensely. 
The  adult  parasites  showed  more  marked  changes,  becoming  round  in  shape, 
while  the  pigment  was  distributed  throughout  the  organisms  or  else  collected 
about  the  periphery;  the  protoplasm  stained  uniformly;  the  chromatin  was  re- 
duced in  amount,  stained  less  intensely  and  the  vesicular  portion  of  the  nucleus 
had  disappeared.  He  found  that  in  the  sporulating  bodies  the  segments  stained 
uniformly,  the  nucleus  slightly,  while  the  unstained  area  was  absent. 

Mannaberg  studied  both  fresh  and  stained  specimens  of  blood.  In  the  for- 
mer he  found  that  amoeboid  motion  became  lessened,  and  that  several  hours 
after  the  administration  of  the  drug  fragmentation  occurred.  In  the  full-grown 
forms  the  pigment  became  immotile,  while  the  protoplasm  became  more  refrac- 
tive and  homogeneous.  In  stained  preparations  he  claimed  that  quinine  causes 
the  chromatin  to  lose  its  power  of  staining  and  in  the  segmenting  forms  most 
of  the  segments  contained  no  chromatin.  Zieman  found  that  when  quinine  is 
administered  during  apyrexia,  the  parasites  become  fragmented,  but  the  chroma- 
tin remains  normal  in  appearance,  while  if  the  drug  be  given  at  the  time  of 
fission  this  process  is  not  hindered,  even  the  chromatin  dividing  as  usual. 

The  Quartan  Plasmodium. — Antolisei,  from  his  observations,  concludes  that 
the  adult  quartan  plasmodium  is  not  affected  by  quinine,  development  and 
sporulation  occurring  as  usual;  but  in  the  attack  following  the  administration  of 
the  drug,  the  young  intracellular  forms  occur  in  much  smaller  numbers. 

Golgi  agrees  with  Antolisei,  but  found  that  the  effect  of  the  drug  upon 
the  young  parasites  varies,  many  being  killed,  while  others  were  hindered  in  their 
development,  which  produced  irregularities  in  the  type  of  fever.  He  claims  that 
the  drug  does  not  affect  the  adult  quartan  parasite. 

Mannaberg  found  that  the  changes  observed  in  the  quartan  plasmodia  after 
the  administration  of  quinine  were  the  same  as  those  observed  in  the  tertian 
Plasmodium. 

The  Aestivo-autumnal  Plasmodia. —  Baccelli  observed  that  in  aestivo- 
autumnal  infections  quinine  produced  an  increase  in  the  amoeboid  movements, 
and  that  the  plasmodia  disappeared  from  the  blood  without  any  degenerative 
changes  being  apparent. 

Marchiafava  and  Bignami,  after  a  careful  study  of  this  subject,  determined 
that  quinine  caused  the  young  plasmodia  to  leave  the  infected  corpuscle,  and  that 
staining  showed  no  evidence  of  morphological  change  after  the  administration 
of  the  drug.  They  state  that  development  is  hindered,  however,  as  shown 
by  the  non-development  of  pigment,  thus  proving  that  nourishment  is  hindered. 
These  authors  believe  that  quinine  not  only  acts  directly  upon  the  plasmodia, 
but  also  modifies  the  erythrocyte  in  such  a  way  that  it  becomes  impossible  for  the 
Plasmodium  to  develop  within  it.  In  conclusion  they  say:  "Quinine  acts  upon 
the  malarial  parasites  in  that  phase  of  their  life  history  in  which  they  are  nour- 
ished and  develop." 

La  Monaco  and  Panichi  claim  that  the  resistance  of  the  plasmodia  to 
quinine  is  greatest  during  the  apyrexial  period,  and  least  at  the  approach  of 
and  during  the  pyrexial.  In  their  experiments  they  found  that  the  effect  of  the 
quinine  varies  with  the  strength  of  the  solution  employed,  weak  solutions  causing 
swelling  of  the  parasites  and  stimulating  amoeboid  motion;  medium  solutions 
greatly  stimulating  movement,  resulting  in  the  extrusion  of  the  plasmodium  frcm 
the  erythrocytes;  while  strong  solutions  caused  contraction  and  death. 


364       DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 

Cappogrossi  concludes  that  the  exit  of  the  plasmodium  from  the  erythrocyte 
is  not  the  result  of  the  specific  action  of  quinine,  but  is  purely  physical,  being  due 
to  the  hypotonicity  of  the  quinine  solution.  He  claims  that  quinine  in  an  iso- 
tonic solution  of  sodium  chloride  does  not  cause  the  plasmodia  to  leave  the  ery- 
throcytes, but  results  in  loss  of  motility,  while  the  protoplasm  becomes  more 
opaque  and  tinted  with  haemoglobin. 

Personal  Observations. — In  considering  the  action  of  quinine  upon  the 
malarial  plasmodia  I  shall  describe  the  changes  occurring  in  each  species,  in 
both  fresh  and  stained  specimens  of  blood. 

Plasmodium  Vivax  (Tertian  Plasmodium). — The  action  of  quinine  upon 
the  tertian  plasmodium  is  evident  in  fresh  blood  specimens  during  every  stage 
of  the  life  cycle  in  man  except  immediately  before  sporulation.  The  changes 
produced  by  the  drug  consist  chiefly  in  a  granular  degeneration  of  the  proto- 
plasm and  fragmentation,  the  latter  being  most  common  in  the  nearly  full- 
grown  parasites.  To  these  changes  should  be  added  a  great  diminution  in  the 
amount  of  pigment  in  the  developing  forms,  thus  showing  a  marked  disturbance 
in  the  nutritive  functions  of  the  organisms. 

The  effect  of  the  drug  varies  with  the  time  of  administration  and  the  dose, 
but  it  is  effective  upon  all  but  the  segmenting  bodies,  and  therefore  is  curative 
whenever  given,  whether  in  one  large  dose  just  before  sporulation  or  in  divided 
doses. 

If  quinine  is  administered  when  the  young  intracorpuscular  plasmodia  are 
present  the  changes  produced  by  it  are  an  increase  in  amoeboid  motion,  followed 
in  an  hour  by  a  decrease  and  finally  by  complete  cessation;  an  increase  in  the 
refractive  quality  of  the  protoplasm;  and  finally  granular  degeneration  of  this 
portion  of  the  plasmodium.  During  the  stage  of  stimulation,  the  amoeboid 
motion  may  become  very  active,  the  pseudopodia  being  projected  so  swiftly 
that  it  becomes  almost  impossible  to  follow  the  process.  After  the  cessation  of 
motion  the  young  plasmodia  become  "ring-shaped"  or  spherical,  and  much 
more  sharply  outlined  than  is  the  normal  tertian  plasmodium.  At  this  stage  of 
growth  no  shrinkage  of  the  organisms  was  observed  as  described  by  Golgi. 

If  now  the  blood  be  examined  at  regular  intervals,  the  quinine  being 
continued,  it  will  be  found  that  the  plasmodia  diminished  greatly  in  number  up 
to  the  time  of  sporulation,  proving  that  at  every  stage  of  their  growth  quinine  is 
capable  of  destroying  them.  Although  this  is  so,  a  considerable  number 
succeed  in  developing  and  finally  reproduce  by  sporulation,  but,  as  will  be  shown 
in  studying  stained  specimens,  even  these  more  fortunate  organisms  develop 
atypically,  as  the  majority  of  the  spores  are  sterile  and  incapable  of  further 
development. 

In  those  plasmodia  which  perish  prior  to  sporulation,  quinine  causes 
fragmentation,  and  eventually  complete  degeneration.  Such  fragmented  para- 
sites are  very  numerous  in  specimens  of  blood  from  tertian  infections  after  the 
administration  of  quinine,  and  in  those  instances  in  which  the  drug  has  been 
given  after  pigment  formation,  fragmentation  is  the  most  common  form  of 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       365 

degeneration,  but  is  always  preceded  by  increased  motility  and  by  an  increased 
refractive  index.  Numerous  erthrocytes  are  observed  containing  plasmodia 
which  are  fragmented,  the  fragments  containing  pigment  in  most  instances. 
The  pigment  may  be  motile  or  immotile,  and  is  collected  in  the  form  of  rather 
large  blocks  or  masses.  The  protoplasm  of  the  fragmented  organism  is  al- 
ways more  refractive  than  that  of  the  normal  tertian  plasmodium,  and  generally 
appears  coarsely  or  finely  granular.  In  many  instances  the  fragmented  para- 
sites are  extruded  in  whole  or  in  part  from  the  red  blood-corpuscles  and  thus 
become  free  in  the  plasma,  from  which  they  quickly  disappear,  and  in  tertian 
infections  after  the  administration  of  quinine  it  is  very  common  to  find  many 
free  degenerated  plasmodia  in  the  blood.  Fragmentation  of  the  tertian  Plasmo- 
dium due  to  quinine  occurs  at  every  stage  in  the  human  life  cycle  of  the  organism 
up  to  the  sporulating  form,  but  in  the  latter  bodies  I  have  never  observed  any 
evidence  of  this  process. 

While  fragmentation  of  the  plasmodia  is  very  often  the  result  of  the  action 
of  quinine  upon  these  parasites,  it  does  not  invariably  occur,  for  many  of  the 
plasmodia  present  certain  changes  which  do  not  eventuate  in  fragmentation. 
These  changes  consist  in  a  marked  shrinkage  in  the  size  of  the  organism,  loss  of 
motility  of  the  pigment,  and  increase  in  the  refractive  index,  together  with 
granular  degeneration  of  the  protoplasm. 

Upon  the  fully  developed  tertian  plasmodium  prior  to  the  beginning  of 
sporulation,  quinine  exerts  a  marked  action,  causing  a  shrinkage  of  the  organism, 
and  a  markedly  granular  appearance  of  the  protoplasm,  while  the  pigment  be- 
comes immotile,  and  is  collected  in  large  clumps  throughout  the  protoplasm  or 
is  distributed  about  the  periphery  in  small  masses.  Fragmentation  may  occur, 
but  it  is  not  as  common  as  in  the  younger  pigmented  forms. 

When  quinine  is  administered  just  at  the  beginning  of  sporulation  it 
produces  no  morphologic  changes  in  the  plasmodia,  but  if  it  has  been  present 
during  the  period  of  growth  of  the  plasmodia  it  will  be  found  that  the  sporulating 
bodies,  which  have  evidently  partially  resisted  the  action  of  the  drug,  are  smaller, 
appear  more  refractive  than  normal,  while  the  number  of  spores  is  reduced. 

There  can  be  no  doubt  that  quinine  is  very  fatal  to  the  young  spores 
resulting  from  segmentation,  while  they  are  yet  free  in  the  blood  plasma,  but  it 
is  not  fatal  to  all  of  them,  for  in  every  case  careful  examination  will  demonstrate 
that  some  escape,  penetrate  the  erythrocytes,  and  undergo  more  or  less  complete 
development.  This  can  be  demonstrated  even  in  those  cases  of  tertian  malaria 
which  do  not  present  clinical  symptoms  of  the  infection,  i.e.,  the  latent  cases. 

From  the  changes  which  have  been  described  it  is  evident  that  if  quinine  is 
administered  when  the  blood  contains  the  young  intracellular  plasmodia  of  ter- 
tian malaria  it  produces  death  in  a  certain  number,  while  others  are  able  to 
develop  more  or  less  perfectly,  but  are  undoubtedly  injured  during  every  stage 
of  their  growth  if  the  drug  be  given  at  regular  intervals.  This  injury  may 
result  in  death  at  a  later  period  of  development  or  by  atypical  development. 
If  sporulation  occurs,  the  spores  are  reduced  in  number,  and.  as  will  be  shown  in 


6 


66       DIAGNOSIS,   PROPHYLAXIS.  AND  TREATMENT  OF  MALARIAL  FEVERS. 


the  description  of  the  stained  specimens,  most  of  them  are  sterile.  Upon  al 
forms  of  the  pigmented  tertian  plasmodium  until  the  beginning  of  sporulation 
quinine  has  a  marked  action,  causing  either  fragmentation,  shrinkage  in  size, 
or  granular  degeneration  of  the  organism.  The  effect  of  the  quinine  upon  all 
stages  of  growth  of  the  plasmodium  is  most  marked  when  it  is  administered  in 
divided  doses  at  regular  intervals  of  time,  thus  keeping  the  blood  supplied  with 
it.  If  given  just  prior  to  the  expected  chill,  in  one  large  dose,  the  majority  of 
the  young  plasmodia  are  destroyed  while  free  in  the  blood  plasma,  but  those 
which  escape  and  develop  present  but  little  evidence  of  the  action  of  the  drug,  as 
would  be  expected,  for  the  blood  is  free  from  quinine  for  several  hours  before  the 
administration  of  the  next  dose. 

In  stained  specimens  of  blood  containing  the  tertian  plasmodium  the  ac- 
tion of  quinine  is  very  clearly  demonstrated.  The  modification  of  Wright's 
method  already  described  was  used  invariably,  and  invariably  the  same  mor- 
phological changes  were  observed  after  the  administration  of  this  drug.  From 
my  observations  I  have  been  able  to  confirm  many  of  Romanowsky's  published 
results,  but  I  have  been  unable  to  demonstrate  that  the  chromatin  of  any  of  the 
species  of  plasmodia  loses  its  staining  properties,  but,  rather,  I  have  found  that 
this  important  portion  of  the  nucleus  stains  even  more  intensely  than  normal, 
but  that  the  brilliant  red  color  is  replaced  by  a  very  dark  violet  or  almost  black. 
While  this  is  true  it  was  invariably  observed  that  the  unstained  portion  of  the 
nucleus  had  disappeared,  and  in  those  plasmodia  which  continued  the  develop- 
mental cycle,  the  chromatin  had  either  failed  to  divide  or  divided  imperfectly, 
many  of  the  spores  showing  no  chromatin,  as  described  by  Mannaberg.  The 
statement  of  Zieman  that  the  chromatin  remains  normal  in  appearance  and 
divides  as  usual  can  only  be  true  of  those  cases  in  which  the  quinine  is  ad- 
ministered just  before  sporulation,  for  if  this  drug  be  given  during  the  formation 
of  pigment  the  vast  majority  of  the  plasmodia  which  live  to  sporulate  present 
either  no  evidence  of  division  of  the  chromatin  or  division  is  imperfect,  only  a 
few  of  the  spores  showing  any  chromatin. 

In  order  to  study  the  morphologic  changes  occurring  in  the  tertian  plas- 
modia as  the  result  of  the  administration  of  quinine  it  is  necessary  that  the  drug 
be  given  in  divided  doses  to  single  tertian  infections,  the  first  dose  just  before 
sporulation;  specimens  of  blood  should  then  be  taken  at  intervals  of  three 
hours  and  immediately  stained.  Given  just  before  sporulation  and  repeated  at 
intervals  of  every  three  hours,  the  quinine  acts  upon  the  plasmodia  not  only 
while  free  in  the  plasma,  but  also  upon  every  stage  of  their  life  cycle  in  man,  and 
it  is  thus  possible  to  study  the  morphologic  changes  produced  by  quinine  in 
every  stage  of  the  development  of  these  organisms. 

The  young,  unpigmented  "ring-forms"  stain  very  intensely  after  the  ad- 
ministration of  quinine,  the  protoplasm  a  much  darker  blue  than  normal,  while 
the  chromatin  stains  a  very  dark  crimson,  often  almost  black.  Besides  the  in- 
crease in  the  intensity  of  the  stain,  the  loss  of  the  unstained  area  about  the 
chromatin  (the  vesicular  portion  of  the  nucleus)  is  very  noticeable,   and  con- 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       367 

stitutes  a  most  important  evidence  of  the  injurious  action  of  the  drug  upon  these 
parasites. 

In  tertian  plasmodia  a  little  further  advanced  in  development,  the  staining 
reactions  are  the  same  as  for  the  "ring-forms,"  but  the  increased  motility  of  the 
plasmodia  is  shown  in  the  great  number  and  "bizarre"  arrangement  of  the 
pseudopodia.  Fragmentation  is  observed  even  before  the  formation  of  pig- 
ment, some  of  the  unpigmented  plasmodia  being  broken  up  into  deeply  stained 
portions,  the  chromatin  lying  in  one  of  these  portions  or  free  near  the  periphery 
of  the  red  cell. 

After  the  formation  of  pigment,  and  especially  after  the  plasmodia  are  from 
one-half  to  three-quarters  grown,  the  evidence  of  fragmentation  and  extrusion 
of  the  chromatin  becomes  more  marked.  Many  of  the  erythrocytes  contained 
deep  blue  portions  of  protoplasm,  the  chromatin  lying  free  within  the  red  cor- 
puscle. The  latter  is  frequently  situated  at  the  extreme  periphery  of  the  red 
cell  or  even  partly  outside  of  it.  At  this  stage  numerous  extracellular  plasmodia 
are  observed,  either  undergoing  fragmentation  or  other  forms  of  degeneration. 
Many  of  the  fragments  are  entirely  devoid  of  pigment,  staining  a  deep  uniform 
blue  throughout,  while  some  may  be  almost  filled  with  blocks  and  granules  of 
pigment.  The  vesicular  portion  of  the  nucleus  is  always  absent,  nor  is  there  any 
evidence  of  an  increase  in  the  amount  of  chromatin  which  is  so  noticeable  in  the 
normal  plasmodium  when  at  this  stage  of  development.  If  fragmentation  be 
absent,  the  protoplasm  of  the  plasmodium  stains  a  very  dark  blue  and  the 
chromatin  a  dark  violet  or  almost  black.  The  pigment  is  generally  collected 
about  the  periphery  of  the  plasmodium.  In  many  instances  the  chromatin  is 
situated  at  the  extreme  periphery  of  the  parasite  or  may  lie  partly  or  wholly  out- 
side of  it  within  the  erythrocyte,  proving  that  quinine  possesses  the  power  of 
causing  extrusion  of  the  chromatin,  thus  rendering  the  plasmodium  sterile. 

Together  with  absence  of  the  vesicular  portion  of  the  nucleus  there  is 
seldom  any  evidence  of  increase  in  the  amount  of  chromatin  and  of  division  of 
the  latter. 

In  fully  developed  tertian  plasmodia  fragmentation  frequently  occurs, 
many  of  the  fragmented  parasites  being  free  from  chromatin,  but  the  character- 
istic change  at  this  period  of  development  in  those  plasmodia  in  wThich  frag- 
mentati:n  is  absent,  as  shown  by  stained  specimens,  lies  in  the  fact  that  although 
the  chromatin  may  be  present  and  stains  an  intense  violet,  it  has  increased  but 
little  or  not  at  all  in  amount,  and  division  is  either  absent  or  imperfect,  only  two 
or  three  small  masses  being  present,  which  lie  close  together  near  the  periphery 
of  the  organism.  In  tertian  plasmodia  which  have  not  been  acted  upon  by 
quinine,  and  have  reached  this  stage  of  development,  the  chromatin  has  always 
greatly  increased  in  amount  and  is  found  divided  into  numerous  masses  which 
are  scattered  throughout  the  protoplasm.  The  morphology  of  the  plasmodia  at 
this  stage  of  their  growth  indicates  clearly  that  quinine  prevents  an  increase  in 
amount  of  chromatin  and  either  hinders  division  or  prevents  it  altogether. 

At  this  stage  the  protoplasm  of  the  plasmodium  stains  a  deep  blue  and  the 


368       DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 

pigment  is  collected  about  the  periphery  in  blocks  or  granules,  or  more  rarely, 
distributed  throughout  the  protoplasm  in  the  form  of  fine  granules  or  small 
clumps.     The  vasicular  portion  of  the  nucleus  is  always  absent. 

Those  plasmodia  which  sporulate  after  having  been  exposed  to  the  action 
of  quinine  throughout  their  entire  cycle  of  development  present  very  marked 
morphological  evidences  of  the  injurious  action  of  the  drug,  in  stained  prepara- 
tions. While  sporulation  may  not  be  entirely  prevented  the  majority  of  the 
spores  are  devoid  of  chromatin,  and  are  undoubtedly  sterile.  The  spores  are 
also  greatly  decreased  in  number  and  may  be  distorted  in  shape,  while  in 
those  which  show  the  presence  of  chromatin  the  latter  is  in  the  form  of  minute 
irregular  masses,  very  distinct  from  the  compact  spherical  mass  observed  in 
normal  parasites.  Very  often  sporulating  bodies  are  observed  in  which  only 
two  or  three  of  the  spores  possess  chromatin;  in  such  spores  the  protoplasm 
stains  a  deep  blue,  the  chromatin  almost  black,  and  there  is  no  evidence  of  the 
vesicular  portion  of  the  nucleus.  Associated  with  the  chromatin  containing 
spores  are  from  six  to  eight,  or  perhaps  more,  deeply  stained  spores  devoid  of 
chromatin.  In  the  sporulating  plasmodia,  the  pigment,  instead  of  being 
collected  in  a  dense  compact  mass,  as  is  the  rule  in  the  normal  tertian  Plas- 
modium, is  reduced  in  amount,  and  scattered  in  small  clumps  or  granules 
between  the  spores. 

From  the  changes  demonstrated  in  stained  specimens  of  tertian  plasmodia 
after  the  administration  of  quinine  it  is  evident  that  this  drug,  administered  in 
divided  doses,  exercises  a  markedly  injurious  effect  upon  every  stage  in  the 
human  life  cycle  of  this  organism,  either  causing  the  death  of  the  parasite  at 
some  period  of  its  development  or  preventing  normal  sporulation  by  restrain- 
ing the  production  and  division  of  the  chromatin  prior  to  segmentation.  The 
death  of  the  organism  is  evidenced  by  fragmentation  or  extrusion  of  the  chroma- 
tin, while  the  effect  upon  sporulation  is  shown  by  the  lessened  production  of 
this  substance,  the  limited  division  of  the  chromatin  present,  and  the  number  of 
spores  which  are  devoid  of  this  essential  portion  of  the  nucleus.  The  loss  of 
the  vesicular  portion  of  the  nucleus  is  probably  responsible  for  the  changes 
which  are  observed. 

If  quinine  is  administered  in  one  large  dose  just  prior  to  segmentation  and 
the  dose  is  not  repeated,  the  changes  produced  are  the  same  in  kind  as  those 
described,  but  a  very  large  number  of  the  plasmodia  escape  entirely  or  are  but 
little  injured.  When  given  in  this  way  segmentation  occurs  as  usual,  and  both 
the  sporulating  bodies  and  the  individual  spores  appear  normal. 

Plasmodium  Malariae  (the  Quartan  Plasmodium). — The  changes 
produced  by  quinine  in  the  quartan  plasmodium,  as  shown  by  both  fresh  and 
stained  preparations  of  blood,  are  practically  the  same  as  those  described  for 
the  tertian  plasmodium,  and  I  cannot  agree  with  Antolisei  and  Golgi  that  upon 
the  adult  quartan  plasmodium  quinine  has  no  effect.  In  the  young  intracellular 
forms  development  is  hindered  or  stopped,  there  being  the  same  initial  stimula- 
tion of  amoeboid  movement,  while  in  the  older  forms  fragmentation  and  degen- 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       369 

eration  occur  as  frequently  as  in  the  tertian  plasmodium.  I  have  not  been  able 
to  observe  any  difference,  so  far  as  morphologic  evidence  goes,  in  the  effect  of 
quinine  upon  the  tertian  and  quartan  plasmodia,  although  it  is  undoubtedly 
true  that  because  of  greater  resistance  to  the  drug,  a  larger  number  of  quartan 
plasmodia  escape  destruction  at  the  time  of  sporulation.  As  in  the  tertian 
infections,  the  effect  of  the  drug  is  most  apparent  when  it  is  administered  in 
divided  doses  at  regular  intervals. 

Plasmodium  Falciparum.  Plasmodium  Falciparum  Quotidianum 
(The  Tertian  and  Quotidian  Aestivo-autumnal  Plasmodia). — As  the  effect 
of  quinine  is  the  same  upon  both  species  of  aestivo-autumnal  plasmodia, 
I  shall  consider  them  together.  As  stated  in  the  historical  summary, 
Marchiafava  and  Bignami  found  that  in  fresh  specimens,  after  the  administra- 
tion of  quinine,  the  plasmodia  assumed  a  discoid  form  and  left  the  erythrocytes, 
while  the  motility  was  normal  or  increased.  While  I  have  been  able  to  confirm 
the  occurrence  of  the  discoid  shape,  I  have  not  been  able  to  confirm  their  ob- 
servations regarding  the  exit  of  the  plasmodia  from  the  red  cells.  The  follow- 
ing observations  are  based  upon  the  study  of  the  action  of  quinine  upon  both 
fresh  and  stained  specimens  of  blood  containing  the  aestivo-autumnal  plas- 
modia, including  every  form  of  the  organisms  except  the  fully  developed 
pigmented  bodies  and  the  sporulating  bodies. 

In  fresh  specimens,  a  few  hours  after  the  administration  of  quinine  in 
divided  doses,  the  time  varying  with  the  rate  of  absorption  of  the  drug,  the 
hyaline  "ring-forms"  become  much  more  refractive  and  sharply  cut  than 
normal  while  the  amoeboid  motion  is  always  greatly  stimulated.  In  most 
instances,  the  "ring-forms,"  owing  to  the  great  increase  in  the  activity  of  the 
amoeboid  motion,  lose  their  distinctive  form,  becoming  discoid  or  assuming 
irregular  shapes,  and  not  infrequently  change  their  position  in  the  red  corpuscle 
very  rapidly,  occupying  the  same  portion  of  the  cell  only  a  few  seconds  at  a 
time,  but  I  have  never  observed  their  exit  from  the  red  corpuscle. 

Upon  the  larger  pigmented  forms,  and  pigmented  "rings"  quinine  appears 
to  have  less  effect,  the  only  change  observed  in  fresh  specimens  being  an 
increase  in  the  refractive  index,  while  the  outline  of  the  plasmodia  becomes 
more  sharply  defined.  I  have  not  observed  degeneration  by  fragmentation  in 
the  aestivo-autumnal  plasmodia,  although  it  is  so  common  in  the  tertian  and 
quartan  parasites. 

In  stained  specimens  the  results  of  my  observations  are  opposed  to  those 
of  Marchiafava  and  Bignami,  who  claim  that  no  morphologic  changes  occur  in 
these  plasmodia  after  the  administration  of  quinine,  and  that  the  unpigmented 
parasites  do  not  become  pigmented  after  its  administration.  I  have  repeatedly 
observed  pigmented  forms  of  both  the  tertian  and  quotidian  aestivo-autumnal 
plasmodia  develop  after  quinine  had  been  administered  for  as  long  as  three 
days,  while  the  morphologic  changes  produced,  though  not  so  marked,  are 
similar  to  those  observed  in  the  tertian  and  quartan  plasmodia. 

In  the  "ring-forms,"  which  are  most  easily  studied,  the  staining  capacity 
24 


370       DIAGNOSIS,   PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 

of  both  the  protoplasm  and  the  chromatin  is  increased,  but  the  unstained  area 
surrounding  the  chromatin  disappears.  A  large  number  of  the  " ring-forms" 
may  appear  normal,  but  careful  examination  will  demonstrate  that  most  of 
them  show  the  loss  of  the  vesicular  portion  of  the  nucleus  and  that  the  "rings" 
are  distorted  in  shape  owing  to  the  increased  amoeboid  motion.  In  a  few 
instances  I  have  observed  the  separation  of  the  chromatin  from  the  body  of  the 
Plasmodia,  thus  proving  that  extrusion  had  occurred.  I  have  never  observed 
fragmentation  of  the  "ring-forms." 

The  changes  produced  in  the  young  pigmented  forms  of  the  aestivo-autum- 
nal  plasmodia,  as  shown  in  stained  preparations,  are  similar  in  every  respect 
to  those  occurring  in  the  tertian  and  quartan  plasmodia,  consisting  in  frag- 
mentation, loss  of  the  vesicular  portion  of  the  nucleus  and  extrusion  of  the 
chromatin. 

Effect  of  Quinine  upon  Gametes  and  upon  Intracorpuscular  Conjuga- 
tion.— No  morphological  changes  occur  in  the  gametes  (crescents)  of  the 
aestivo-autumnal  plasmodia  so  far  as  can  be  observed  in  both  fresh  and  stained 
preparations,  and  Marchiafava,  Gualdi,  and  Martirano  have  proven  that  the 
crescents  are  not  destroyed  by  quinine  and  that  they  are  still  capable  of  under- 
going development  wathin  the  mosquito,  after  quinine  has  been  administered, 
for  long  periods  of  time.  Crescents,  however,  do  not  appear  if  quinine  be 
thoroughly  given  during  the  first  attack  of  an  aestivo-autumnal  infection,  a 
fact  well  known  to  every  student  of  the  aestivo-autumnal  fevers. 

As  regards  the  effect  of  quinine  upon  the  tertian  gametes,  Schoo,  in  Holland, 
has  demonstrated  that  quinine  prevents  the  development  of  the  tertian  gamete 
in  the  mosquito;  his  experiments  follow: 

A  case  of  tertian  fever  was  bitten  by  a  large  number  of  Anopheles,  all 
becoming  infected.  One  gm.  of  quinine  was  then  administered  for  three  days, 
and  1 6  Anopheles  allowed  to  bite,  none  becoming  infected. 

A  case  of  tertian  malaria  was  bitten  by  10  Anopheles  during  the  afebrile 
period,  of  which  eight  became  infected.  Four  hours  before  the  chill  he  was 
given  i  gm.  of  quinine,  and  six  hours  afterward  was  bitten  by  nine  Anopheles, 
of  which  none  became  infected. 

Upon  the  quartan  gametes  we  possess  no  evidence  showing  that  quinine 
is  capable  of  preventing  their  development  in  the  mosquito. 

In  both  tertian  and  quartan  infection  the  prompt  administration  of  quinine 
during  the  first  attack  of  fever  will  prevent  the  development  of  the  gametes. 

Upon  intracorpuscular  conjugation  quinine  has  a  fatal  influence,  for,  after 
the  administration  of  this  drug,  conjugating  plasmodia  entirely  disappear  from 
the  peripheral  blood  and  do  not  reappear  unless  the  administration  has  been 
stopped,  and  then  only  after  an  interval  of  days  or  even  weeks.  Even  in  those 
instances  in  which  the  drug  is  given  in  such  small  doses  as  to  injure  but  slightly 
the  developing  plasmodia,  the  conjugating  organisms  quickly  disappear,  and 
as  the  process  of  conjugation  is  undoubtedly  intended  to  assist  in  maintaining 
malarial  infection,  the  marked  action  of  quinine  upon  it  offers  another  explana- 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       37 1 

tion  of  the  efficiency  of  the  drug  in  curing  these  fevers  if  it  be  properly  given 
during  the  initial  attack. 

From  the  evidence  submitted  I  believe  that  it  is  an  incontrovertible  fact 
that  quinine  is  a  true  specific  for  the  malarial  fevers,  acting  directly  upon  the 
Plasmodia  causing  these  fevers,  during  every  stage  of  their  human  life  cycle, 
except  the  presegmenting  stage,  and  that  its  persistent  administration  will 
invariably  result  in  the  cure  of  any  malarial  infection,  provided  the  drug  be 
properly  administered. 

2.  Choice  of  Preparation. — Of  the  eighteen  or  more  salts  of  quinine 
which  have  been  used  in  the  treatment  of  the  malarial  fevers,  but  a  very  limited 
number  are  deserving  of  attention,  in  that  they  are  of  practical  use.  The  most 
useful  are  the  sulphate  and  the  bihydrochloride  or  bimuriate  of  quinine.  Of 
these  two  salts  the  bihydrochloride  is  the  more  soluble,  being  dissolved  in  the 
proportion  of  1  part  to  .96  parts  of  water,  while  the  sulphate  is  only  soluble  in 
1  to  800  parts  of  water.  Of  the  two  salts  the  sulphate  is  the  more  used,  as  it 
is  much  cheaper  and  can  be  procured  more  easily.  The  following  table  of  the 
chief  salts  of  quinine  and  their  solubility  will  prove  useful  to  the  therapeutist, 
but  practically  it  will  be  found  that  the  sulphate  is  most  useful  in  the  vast 
majority  of  our  cases  of  malarial  fever. 


Salt 


Alkaloid 

in  salt 

73 

5 

% 

81 

8 

% 

72 

0 

% 

76 

6  % 

60 

0 

% 

59 

1 

% 

76 

2 

% 

73 

0 

% 

78 

2 

% 

70 

1 

% 

69 

4 

% 

20 

0 

% 

Solubility  in  cold  water 


Sulphate     

Hydrochloride 
Bihydrochloride 
Hydrobromide 
Bihydrobromide 

Bisulphate 

Phosphate 

Valerianate .... 

Lactate    

Salicylate 

Arseniate 

Tannate      


In  800  parts. 

In  40  parts. 

In  .96  parts. 

In  45  parts. 

In     7  parts. 

In  11  parts. 

In  420  parts. 

In  120  parts. 

In  10  parts. 

In  225  parts. 

Very  slightly  soluble. 

Very  slightly  soluble. 


For  hypodermic  use  the  bihydrochloride  or  bimuriate  of  quinine  is  most 
commonly  employed,  but  the  bihydrobromide,  the  lactate,  and  the  bichloride 
of  quinine  and  urea  may  also  be  used  for  hypodermic  injection. 

3.  Time  of  Administration. — The  time  of  administration  of  quinine  in 
malarial  infections  has  been  the  subject  of  much  discussion,  but  from  what 
we  know  of  the  action  of  the  drug  upon  the  malarial  plasmodia  it  is  difficult 
to  see  why  this  should  be  so.  As  I  have  shown,  the  drug  acts  upon  every  stage 
in  the  development  of  all  the  species  of  plasmodia  except  the  presegmenting 


3  7  2       DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 

stage  and  therefore  it  is  evident  that  if  the  blood  constantly  contains  the  drug 
the  best  effects  will  be  secured.  Those  who  advocate  the  administration  of 
quinine  in  one  large  dose  just  before  the  expected  paroxysm,  trusting  that  all  of 
the  newly  developed  spores  will  thus  be  killed,  lose  sight  of  this  fact,  and  also 
of  the  fact  that  many  of  the  spores  escape  when  the  drug  is  thus  administered. 
While  in  tertian  and  quartan  infections,  in  which  the  paroxysms  occur  at  regular 
intervals,  good  results  may  be  obtained  by  giving  the  quinine  in  one  large  dose 
during  the  decline  in  the  temperature,  in  aestivo-autumnal  infections  and  in 
irregular  tertian  and  quartan  infections  the  best  results  are  obtained  when  the 
drug  is  given  in  divided  doses  at  regular  intervals,  and  I  have  found  from 
personal  experience  that  the  latter  method  of  administration  is  preferable  in 
all  cases  of  malarial  infection. 

It  is  not  necessary  to  discuss  here  the  many  contributions  to  the  literature 
of  malaria  dealing  with  this  subject,  but  those  interested  should  consult  the 
valuable  paper  of  Dock  which  contains  a  summary  of  the  opinions  of  various 
writers  upon  the  administration  of  quinine  in  malaria.  From  the  studies 
of  the  action  of  this  drug  upon  the  plasmodia  it  is  evident  that  in  order  to  secure 
the  best  therapeutic  results  the  drug  should  be  present  in  the  blood  continually, 
and  therefore  it  should  be  administered  in  divided  doses  at  regular  intervals  of 
time.  Given  in  divided  doses  at  regular  intervals  the  blood  constantly  contains 
a  sufficient  quantity  to  practically  stop  the  development  of  the  plasmodia  which 
have  succeeded  in  escaping  it  while  free  in  the  blood  plasma,  and  recovery  is 
thereby  hastened. 

The  practice  of  giving  quinine  in  the  manner  mentioned  is  not  only  justi- 
fied by  the  morphologic  changes  observed  in  the  plasmodia,  but  its  value  is 
proven  by  practical  experience.  Manson  recommends  the  administration  of 
quinine  in  divided  doses,  and  many  tropical  practitioners  have  found  that  this 
is  the  most  successful  method  of  administration.  I  have  at  present  the  records 
of  over  2,000  malarial  cases  (mostly  in  the  person  of  soldiers  of  our  army, 
returning  from  the  Philippines  and  serving  in  the  Philippines),  including 
tertian,  quartan,  and  aestivo-autumnal  infections,  in  which  quinine  was 
administered  in  doses  of  0.50  gm.  every  three  hours  until  from  1.50  to  2.00  gms. 
were  taken,  and  in  all  of  these  cases  recovery  was  prompt  and  occurred  more 
quickly  than  in  similar  cases  in  which  one  large  dose  of  the  drug  was  adminis- 
tered prior  to  sporulation.  In  the  tertian  cases  it  was  very  rarely  that  a  second 
chill  occurred  after  the  beginning  of  the  administration  of  the  drug,  although 
in  about  20  per  cent,  of  the  cases  a  rise  of  a  temperature  was  noted  upon  the 
day  of  the  expected  paroxysm.  In  the  quartan  cases  a  second  paroxysm 
never  occurred  after  the  beginning  of  the  administration  of  quinine  in  this  way; 
while  in  the  aestivo-autumnal  cases,  which  comprised  nearly  two-thirds  of 
the  total  number  of  cases,  the  temperature,  except  in  two  pernicious  cases, 
reached  normal  in  from  two  to  three  days  and  recovery  followed.  It  is  in  the 
latter  type  of  malarial  infection  that  the  administration  of  quinine  in  divided 
doses  is  especially  efficient,  for  in  this  type  it  is  generally  impossible  to  tell  the 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       373 

exact  time  of  the  ensuing  paroxysm,  and  thus  it  is  impossible  to  attack  the 
Plasmodia  while  they  are  free  in  the  blood  plasma  by  the  administration  of  one 
large  dose  of  the  drug.  In  these  infections  it  is  necessary  to  give  quinine  in 
divided  doses  of  from  0.30  to  0.60  gm.  (5  to  10  grains)  at  intervals  of  four  to  six 
hours  until  the  temperature  reaches  normal,  and  to  increase  the  number  of 
doses  if  experience  shows  that  the  quantity  advised  is  insufficient.  When  the 
temperature  reaches  normal  the  quinine  should  be  administered  in  one  large 
dose  at  bedtime  or  in  smaller  divided  doses  during  the  twenty-four  hours. 
In  pernicious  and  irregular  forms  of  the  malarial  fevers,  especially  if  due  to  the 
aestivo-autumnal  plasmodia,  the  administration  of  the  drug  should  not  be 
delayed,  but  it  should  be  given  hypodermically  in  doses  of  1  gm.  (15  grains), 
repeated  in  three  hours  if  necessary. 

In  tertian  and  quartain  infections  the  drug  should  preferably  be  given  in 
divided  doses,  but  nearly  as  good  results  will  be  secured  if  it  be  administered  in 
one  large  dose  during  the  decline  in  the  temperature  or  at  the  end  of  pyrexia. 
Given  in  this  way  the  next  paroxysm  will  be  prevented  in  the  majority  of  the 
cases  as  the  drug  has  thus  been  brought  in  contact  with  the  free  spores  upon 
which  it  acts  most  vigorously.  In  all  such  cases  the  sulphate  administered 
in  solution  or  in  capsules  will  be  found  the  cheapest  and  most  efficient  prepara- 
tion. Quinine  should  not  be  discontinued,  even  in  the  mildest  cases  of  malaria, 
after  apparent  recovery,  but  should  be  given  in  doses  of  from  0.30  to  0.60  gm. 
(  5  to  10  grains)  daily  for  at  least  a  week  and  once  a  week  in  doses  of  0.60  gm. 
(10  grains)  for  at  least  two  months  afterward.  Unless  some  such  plan  is 
adopted  recurrences  are  bound  to  occur  and  may  lead  to  chronic  malarial 
cachexia. 

4.  Methods  of  Administration. — Quinine  may  be  administered  by  the 
mouth,  by  the  rectum,  intravenously,  and  hypodermically.  Inunctions  through 
the  skin  have  been  practised  in  rare  instances,  but  are  of  little  practical  impor- 
tance. In  the  vast  majority  of  cases  of  malarial  infection  the  administration 
of  quinine  by  the  mouth  will  be  found  the  most  practicable  method  of  using  the 
drug. 

Administration  by  the  Mouth.— There  are  comparatively  few  cases  in 
which  quinine  cannot  be  administered  by  the  mouth.  In  pernicious  cases,  in 
patients  who  appear  to  be  unable  to  absorb  the  drug  from  the  stomach,  and 
in  those  very  rare  instances  in  which  the  drug  so  deranges  the  stomach  as  to 
produce  grave  symptoms  of  poisoning,  quinine  will  have  to  be  administered  in 
some  other  way,  but  in  the  vast  majority  of  our  cases  of  malaria  the  drug  may 
be  given  by  the  mouth.  When  administered  in  this  way  quinine  may  be  given 
in  the  form  of  pills,  tablets,  wafers,  capsules,  and  solutions.  The  drug  should 
never  be  given  in  pill  or  tablet  form  unless  we  can  be  sure  that  these  are 
readily  soluble,  and  in  most  instances  it  will  be  found  that  the  pills  and  tablets  of 
quinine  ordinarily  found  in  drug  houses  are  very  insoluble,  and  therefore  the 
use  of  the  drug  in  these  forms  should  be  avoided  if  possible.  The  best  form 
in  which  to  administer  quinine  is  in  solution,  but  on  account  of  the  intensely 


374       DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 

bitter  taste  this  method  is  often  inapplicable,  and  then  we  should  administer 
it  in  capsules  or  in  wafers.  I  have  found  from  experience  that  to  secure  good 
results  in  the  treatment  of  malaria  quinine  should  never  be  administered  in  the 
form  of  pills  or  tablets,  and  that  the  best  results  are  secured  when  it  is  adminis- 
tered in  solution. 

When  solutions  are  used,  the  sulphate  is  most  frequently  employed,  a  drop 
of  dilute  hydrochloric  or  sulphuric  acid  being  added  for  every  0.065  (gram)  °f  the 
drug.  The  bitter'  taste  of  the  solution  may  be  partially  disguised  by  the  addi- 
tion of  verba  santa,  or  a  chocolate  syrup,  to  the  solution.  For  children  and  for 
those  who  are  very  easily  nauseated  by  the  bitter  taste  of  quinine,  the  adminis- 
tration of  the  drug  in  the  form  of  chocolate  troches  containing  the  tannate  of 
quinine  is  indicated,  and  in  Italy  the  combination  of  chocolate  with  quinine  has 
been  adopted  by  the  Government  as  the  most  palatable  method  of  dispensing 
the  drug  to  children  and  is  the  form  in  which  the  quinine  issued  by  the  Govern- 
ment is  always  dispensed. 

Administration  by  the  Rectum. — The  administration  of  quinine  through  the 
rectum  has  been  advocated  by  some  authorities,  but  will  be  found  most  unsatis- 
factory in  practice.  This  method  is  recommended  in  children,  but  is  much  more 
disagreeable  to  them  than  the  administration  of  the  drug  by  the  mouth  in  the 
form  of  a  cholcolate  syrup  containing  it  or  chocolate  troches  containing  the 
tannate.  By  the  rectum  absorption  is  very  slow,  a  much  larger  dose  of  the  drug 
has  to  be  given,  and  rectal  irritability  and  pain  is  almost  certain  to  occur. 
When  the  drug  is  given  in  this  way  the  dose  should  be  one-half  again  as  much 
as  when  given  by  the  mouth,  and  should  be  prepared  in  the  form  of  a  rectal  sup- 
pository. If  given  in  solution  by  the  rectum  an  enema  of  150  to  250  c.c.  of 
sterile  salt  solution  should  be  given  containing  the  dose  of  the  drug,  with  from 
five  to  ten  drops  of  tincture  of  opium  added. 

Cutaneous  Inunctions. — Feuchtwanger  and  Rasch  have  advocated 
cutaneous  inunctions  of  quinine  in  children,  but  this  method  is  only  mentioned 
to  be  condemned,  as  the  absorption  of  the  drug  is  so  slow  that  but  little  can  be 
expected  from  this  form  of  administration  in  well  marked  cases  of  malaria,  and 
we  possess  so  many  other  and  better  methods  of  administration  in  this  class  of 
patients  that  cutaneous  inunctions  are  undeserving  of  consideration.  The 
chocolate  tablets  containing  tannate  of  quinine  will  be  found  the  easiest  method 
of  administering  this  drug  to  children,  but  it  should  be  remembered  that  the 
tannate  is  very  slowly  absorbed  and  that  the  dose  should  be  twice  that  of  the 
sulphate. 

Administration  by  the  Hypodermic  Syringe  Subcutaneously.— In  the 
pernicious  forms  of  the  malarial  fevers  and  in  those  cases  in  which,  for  any 
reason,  the  drug  cannot  be  administered  by  the  mouth,  the  hypodermic  injec- 
tion subcutaneously  of  the  more  soluble  salts  of  quinine,  such  as  the  bihydro- 
chloride,  the  bihydrobromide,  and  the  bichloride  of  quinine  and  urea  is  indi- 
cated. When  these  cannot  be  secured  the  bisulphate,  which  is  soluble  in  n 
parts  of  water,  may  be  employed  for  hypodermic  injection.     The  following 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  EEVERS.       375 

solution  I  have  found  most  useful  in  treating  malaria  by  the  hypodermic  in- 
jection of  quinine: 

B Hydrochloride  of  quinine,  5  gm.  (gr.  lxxv) 
Distilled  water,  add  10  gm.  (3iiss) 

In  this  solution  1  c.c.  (15  m.)  contains  0.5  gm.  (grs.  viiss)  of  quinine. 

In  giving  hypodermic  injections  of  quinine  the  utmost  care  should  be  taken 
that  everything  used  in  the  operation,  as  well  as  the  skin  of  the  patient  is  sterile, 
as  abscesses  and  extensive  necrosis  of  the  skin  is  apt  to  occur,  and  even  tetanus 
may  develop  after  the  use  of  a  dirty  syringe  or  a  septic  solution.  The  syringe 
used  should  be,  if  possible,  constructed  entirely  of  glass,  with  the  exception,  of 
course,  of  the  needle,  and  should  be  boiled  for  15  minutes  before  use.  The 
quinine  should  be  placed  in  sealed  glass  tubes  and  sterilized  in  a  hot-air  chamber. 
The  skin  over  the  region  to  be  injected,  preferably  the  back  or  buttock,  is 
thoroughly  cleaned  with  soap  and  water,  then  scrubbed  with  ether,  and 
finally  with  alcohol,  and  the  injection  should  be  made  deep  into  the  subcutane- 
ous tissues,  as  otherwise  necrosis  of  the  skin  is  of  frequent  occurrence.  The 
intramuscular  method  of  injection  is  best.  If  the  materials  used  in  the  opera- 
tion are  sterile,  abscess  formation  will  not  occur,  but  despite  our  greatest  care 
there  is  generally  much  discomfort  and  pain  following  the  injections  and  a  con- 
siderable amount  of  induration  frequently  occurs  about  the  site  of  the  injection. 

Owing  to  the  possibility  of  abscess  formation  and  the  pain  and  discom- 
fort arising  from  the  injections,  this  method  of  administration  of  quinine  should 
not  be  used  save  in  cases  in  which  it  is  essential  to  secure  the  effect  of  the  drug 
rapidly,  as  when  pernicious  symptoms  develop  and  where,  for  any  reason,  such 
as  unconsciousness  or  inability  to  retain  the  quinine,  it  is  impossible  to  give  the 
drug  by  the  mouth.  The  tendency  of  many  practitioners  in  late  years  to 
administer  quinine  hypodermically  in  most  of  their  cases  of  malaria  is  to  be 
deplored,  for  it  is  but  rarely  that  the  drug  cannot  be  administered  with  good 
results  by  the  mouth. 

After  injecting  the  quinine  solution  the  wound  made  by  the  syringe  needle 
should  be  carefully  washed  with  alcohol  and  sealed  with  a  collodion  dressing. 
The  dose  of  the  drug  hypodermically  is  0.5  gm.  (gr.  viiss),  repeated  every  four 
hours  if  necessary. 

Intramuscular  Injection. — Koch  advocates  the  intramuscular  injection 
of  quinine  in  cases  of  recurrent  malaria  and  in  severe  cases  of  aestivo-autumnal 
infection,  even  though  pernicious  symptoms  be  absent.  He  states  that  the 
dose  required  is  less  than  one-half  that  by  the  mouth  and  that  the  infection  is 
cured  more  quickly  and  recurrences  are  less  apt  to  occur. 

The  gluteal  muscles  are  used  for  intramuscular  injections,  and  the  solution 
used  is  the  same  as  for  hypodermic  injection,  the  same  precautions  being  used  as 
regards  the  prevention  of  injection.  Maurer  and  Schiiffer  use  the  bimuriate  of 
quinine  in  equal  parts  of  water  and  glycerine  for  intramuscular  injection,  and 
claim  that  with  this  solution  there  is  but  little  danger  of  abscess  formation. 


376       DIAGNOSIS,   PROPHYLAXIS.  AND  TREATMENT  OF  MALARIAL  TEVERS. 

Intravenous  Injection  of  Quinine. — To  Baccelli  we  owe  this  method  of 
administering  quinine.  It  is  indicated  whenever  we  desire  the  most  prompt 
effect  of  the  drug,  as  in  comatose  cases;  pernicious  cases  after  one  pernicious 
paroxysm  has  been  succeeded  by  another;  when  the  patient's  strength  is  rapidly 
failing;  or  when  other  treatment  has  proved  unavailing.  Marchiafava  and 
Bignami  urge  the  value  of  this  method  especially  in  the  algid  forms  of  pernicious 
malaria.  The  following  solution  will  be  found  most  uesful  when  it  is  desired  to 
give  the  drug  intravenously: 

Bihydrochloride  of  quinine,  1  gm.  (grs.  xv) 

Chloride  of  Sodium,  °-°75  (grs.  iss) 

Distilled  water,  10  gm.  (oiiss) 

This  solution  should  be  perfectly  clear  and  the  entire  amount  is  to  be  in- 
jected, the  fluid  being  Luke-warm.  In  injecting,  the  veins  of  the  forearm  are 
made  prominent  by  a  circular  tourniquet  and  one  of  the  most  prominent  selected 
for  the  injection.  The  same  precautions  are  observed  regarding  asepsis  as 
described  already,  and  the  needle  is  introduced  from  below  upward  into  the 
lumen  of  the  vein.  The  injection  is  made  slowly  and  when  the  entire  amount  is 
injected  the  site  of  puncture  is  sealed  with  collodion.  Extreme  care  must  be 
taken  that  no  air  is  introduced  into  the  vein,  and  that  the  needle  is  sterile,  as  well 
as  the  solution.  The  dose  may  be  repeated  if  necessary.  By  this  method  the 
mortality  of  the  pernicious  malarial  fevers  has  been  markedly  reduced  and  it 
should  always  be  adopted  in  those  cases  which  have  resisted  other  forms  of 
treatment  or  which  require  the  immediate  effect  of  quinine.  Baccelli  states  that 
whereas  before  the  use  of  intravenous  injections  of  quinine  the  mortality  in  those 
cases  of  pernicious  malaria  treated  by  the  hypodermic  method  of  administration 
was  17  per  cent.,  with  his  method  the  mortality  has  been  reduced  to  less  than 
6  per  cent.,  and  his  conclusions  are  confirmed  by  those  of  many  other  observers. 

5.  The  Amount  of  Quinine  to  be  Administered. — There  is  no  doubt 
that  we  err  more  often  upon  the  side  of  excess  in  the  administration  of 
quinine  than  vice  versa,  and  in  most  cases  of  malaria  too  much  of  the  drug  is 
usually  given.  It  is  not  uncommon  to  observe  the  use  of  from  5  to  6  grammes 
of  the  drug  during  the  24  hours,  even  in  the  mildest  cases  of  tertian  and  quartan 
fever,  and  a  general  impression  appears  to  prevail  in  the  profession  that  the 
malarial  fevers  require  massive  doses  of  quinine  in  their  treatment.  The 
employment  of  the  large  amount  mentioned  above  is  entirely  unnecessary 
and  simply  makes  the  patient  more  miserable  while  undergoing  treatment. 
It  should  be  remembered  that  it  is  as  much  the  manner  in  which  the  quinine 
is  administered  as  it  is  the  dose,  which  counts  in  the  treatment  of  malaria, 
and  that  the  use  of  over  40  grains  of  quinine  in  the  24  hours  is  never  necessary, 
even  in  the  treatment  of  the  most  severe  infection.  From  personal  experience 
I  believe  that  2  grammes  (30  grains)  of  quinine,  administered  in  divided  doses 
each  24  hours,  is  amply  sufficient  to  cure  any  ordinary  case  of  aestivo- 
autumnal  infection,  while  in  tertian  and  quartan  infections  a  single  dose  of 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       377 

i  gramme  (15  grains)  will  prevent  the  next  paroxysm,  and  the  same  amount, 
administered  in  divided  doses  during  the  24  hours,  will  eventually  cure  the 
infection.  In  my  experience  with  the  aestivo-autumnal  infections  I  have 
yet  to  see  a  single  case  in  which  treatment  was  begun  in  time  that  did  not 
recover  in  a  few  days  when  treated  with  2  grammes  of  quinine  during  the  24 
hours,  and  I  have  seen  scores  recover  rapidly  when  but  1.3  grammes  (xx  grains) 
of  the  drug  was  administered  during  the  24  hours. 

When  the  drug  is  used  hypodermically  a  dose  of  0.5  gm.,  or  7  1/2  grains, 
should  be  administered  and  repeated,  if  necessary,  until  about  1.5  gm.  (grs.  24) 
have  been  injected.  Some  very  severe  cases  may  require  more  than  this  amount, 
but  they  will  be  rare,  and  in  such  instances  the  intravenous  methods  of  adminis- 
tration should  be  adopted. 

As  soon  as  the  active  symptoms  of  the  paroxysm  have  subsided  the  dose 
of  quinine  may  be  gradually  diminished,  but  the  drug  should  be  used  for 
several  weeks  thereafter,  as  otherwise  recurrences  are  bound  to  occur  in  the 
majority  of  cases.  I  have  found  the  following  doses  of  quinine  efficient  in 
curing  most  of  the  malarial  infections  with  which  I  have  come  in  contact,  and 
it  is  rarely  that  the  doses  as  given  will  need  to  be  increased. 

In  tertian  and  quartan  infections,  in  which  the  paroxysms  occur  at  regular 
intervals,  namely,  in  single  infections,  the  attack  may  be  promptly  cured  by 
the  administration  of  1  to  2  gms.  (15  to  30  grains)  of  quinine  by  the  mouth 
during  the  decline  of  the  temperature,  and  the  dose  repeated  upon  the  following 
day,  or  (and  I  have  found  this  method  preferable)  the  same  amount  of  quinine 
is  given  in  0.32  gm.  (5  grains)  doses  every  four  hours  until  1  to  2  gms.  are  given 
and  the  active  symptoms  disappear.  For  a  period  of  at  least  one  month 
the  drug  should  be  given  in  gradually  decreasing  doses,  thus  preventing  a 
recurrence.  In  cases  of  tertian  and  quartan  infection  in  which,  because  of 
double  or  mixed  infections,  it  is  impossible  to  foretell  the  time  of  the  paroxysm, 
quinine  should  be  administered  as  in  aestivo-autumnal  infections. 

In  aestivo-autumnal  infections  quinine  should  be  given  by  the  mouth  in 
doses  of  0.32  gm.  (grs.  5)  every  four  hours  until  the  active  symptoms  dis- 
appear and  every  five  or  six  hours  afterward  for  a  period  of  three  days.  During 
the  next  week  the  drug  should  be  administered  in  doses  of  1  gm.  (15  grains) 
at  bedtime  on  every  other  day,  and  for  at  least  two  months  thereafter 
upon  the  evening  of  every  sixth  day.  If  the  drug  be  thus  administered  a 
definite  cure  of  the  vast  majority  of  the  aestivo-autumnal  infections  may  be 
predicted.  In  cases  showing  pernicious  symptoms  quinine  should  always  be 
given  hypodermically. 

One  of  the  most  serious  mistakes  made  in  the  treatment  of  the  malarial 
fevers  is  the  abandonment  of  quinine  after  the  disappearance  of  the  active 
symptoms,  and  this  mistake  is  responsible  for  recurrences  and  the  continuation 
of  malarial  infection  in  many  localities.  The  malarial  infections  are  resistant 
to  treatment,  especially  the  aestivo-autumnal  fevers,  and  while  a  few  days' 
treatment  with  quinine  will  cause  the  disappearance  of  the  symptoms,  a  limited 


378       DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 

number  of  the  plasmodia  may  escape,  and  multiplying  gradually,  will  cause 
a  recurrence  of  the  infection.  In  all  malarial  infections,  and  especially  in  the 
aestivo-autumnal  fevers,  quinine  should  be  administered  in  the  manner  suggested 
for  several  weeks  after  all  evidence  of  the  infection  has  disappeared,  and  only 
by  so  doing  can  we  be  sure  that  recurrences  will  not  occur.  This  is  a  lesson  which 
the  physician  in  malarial  localities  seems  to  have  hardly  appreciated  as  yet, 
and  it  is  most  important,  both  from  a  therapeutic  and  prophylactic  standpoint. 

In  view  of  the  researches  of  Ehrlich  and  Browning  upon  the  production 
of  strains  of  trypanosomes  resistant  to  certain  drugs  which  are  usually  cura- 
tive, this  resistance  being  produced  by  insufficient  dosage  of  the  drug,  and 
followed  by  relapses  of  the  injection,  it  would  appear  that  a  similar  resistance 
to  quinine  may  be  acquired  by  the  malarial  plasmodia,  and  this  may  explain 
the  cases  of  malarial  infection  characterized  by  numerous  relapses  and  resis- 
tance to  this  drug.  Reasoning  from  analogy  it  is  reasonable  to  believe  that 
the  malarial  plasmodia,  like  the  trypanosomes,  may  become  resistant  to  certain 
chemicals  which  ordinarily  are  fatal  to  them. 

Quinine  should  never  be  administered  during  the  height  of  a  malarial 
paroxysm,  except  in  pernicious  cases,  as  the  drug  will  greatly  increase  the 
discomfort  of  the  patient,  and  can  be  as  well  given  during  the  decline  in  the 
temperature,  when  it  will  prove  practically  as  effectual,  as  if  given  during  the 
height  of  the  fever.  This  is  a  point  of  some  importance  in  the  treatment  of 
malaria  in  children  and  in  nervous  individuals,  in  whom  I  have  observed  violent 
maniacal  delirium  follow  the  administration  of  large  doses  of  quinine  at  the 
height  of  the  paroxysm.  In  the  treatment  of  malaria  in  children  under  one 
year  of  age  0.032  to  0.065  gm-  (§rs-  iss  to  i)  f°r  a  dose  is  sufficient,  the  dose  to  be 
repeated  as  in  the  adult.  In  older  children  the  drug  is  better  borne  and  should 
be  used,  without  hesitation,  in  large  doses  in  pernicious  attacks. 

6.  Contradictions  to,  and  Substitutes  for  Quinine. — In  rare  instances 
the  administration  of  quinine  is  contraindicated  in  malarial  fever  because  the 
drug  produces  such  dangerous  symptoms  that  it  cannot  safely  be  used.  It  has 
been  the  experience  of  most  physicians  that  many  patients  suffering  from 
these  fevers  protest  against  the  use  of  the  drug,  claiming  that  they  are  unable 
to  take  it  because  of  the  dangerous  symptoms  produced  in  their  case.  In  most 
instances  it  will  be  found  that  these  patients  can  take  quinine,  and  that  the 
belief  that  they  cannot  is  founded  upon  nothing  more  than  a  vivid  imagination. 
If  the  physician  be  firm  in  insisting  upon  the  use  of  the  drug  most  of  these 
patients  will  be  found  able  to  take  large  doses  with  no  more  than  the  usual 
disagreeable  effects.  Idiosyncrasy  to  quinine,  however,  does  exist  in  certain 
individuals,  and  therefore  some  substitute  for  the  drug  must  be  administered. 

In  nearly  all  individuals  the  use  of  moderately  large  doses  of  quinine 
produce  unpleasant  symptoms,  such  as  tinnitus  aurium,  vertigo,  confusion  of 
thought,  slight  deafness,  or  congestion  of  the  cerebral  blood-vessels  and  headache. 
In  very  susceptible  persons  these  symptoms  may  be  produced  by  very  small 
doses  of  the  drug,  and  I  have  observed  one  case,  a  delicate  girl  of  18  years  of 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       379 

age,  in  which  1  /4  of  a  grain  of  sulphate  of  quinine  produced  the  above  symptoms- 
Such  symptoms,  however,  do  not  contraindicate  the  use  of  quinine,  but  when 
amaurosis,  total  deafness,  syncope,  dyspnoea,  alarming  irregularily  of  the 
heart,  haematuria,  and  severe  bleeding  from  the  bowels  and  mucous  membrane 
occur,  the  quinine  should  be  discontinued  and  one  of  the  substitutes  to  be 
mentioned  should  be  administered.  The  question  of  the  production  of  haemo- 
globinuria  by  quinine  will  be  fully  discussed  in  the  section  upon  haemoglobinuric 
fever,  but  it  may  be  stated  here  that  very  rarely  quinine  does  produce  haemo- 
globinuria  and  that  in  cases  in  which  there  is  a  history  of  such  a  condition 
following  its  administration,  the  drug  should  not  be  used. 

Certain  eruptions  of  the  skin  sometimes  follow  the  use  of  quinine,  even  in 
small  doses,  the  most  common  of  which  are  erythema  and  urticaria,  the  latter,  in 
some  instances,  being  very  severe.  Extensive  desquamation  of  the  epidermis  is 
rarely  observed,  one  case  coming  to  my  attention  peeling  so  extensively  that 
practically  the  entire  epidermis  of  the  body  was  replaced.  Almost  perfect  casts 
of  the  hands  and  feet,  composed  of  epidermis,  were  obtained  in  this  case,  and  in 
several  other  cases  I  have  observed  considerable  desquamation  following  the  use 
of  this  drug. 

F.  Plehn  has  described  a  condition  which  he  has  called  "quinine  fever" 
occurring  in  those  who  have  taken  the  drug  for  long  periods  of  time,  and  he 
believes  that  it  is  due  to  the  destruction  of  the  red  blood-corpuscles  by  the  drug 
and  the  consequent  absorption  of  toxic  substances.  While  such  a  form  of  fever 
may  occur  in  certain  localities,  and  among  certain  races,  it  must  be  very  rare,  as 
in  thousands  of  cases  of  malaria  observed  in  the  United  States,  Cuba,  and  the 
Philippine  Islands,  I  have  never  observed  the  occurrence  of  this  form  of  fever. 

The  use  of  quinine  in  the  treatment  of  malaria  during  pregnancy  deserves 
attention.  It  is  an  undoubted  fact  that  in  women  who  abort  easily  this  drug  is 
capable,  in  considerable  doses,  of  producing  miscarriage,  but  it  is  also  true  that 
repeated  malarial  paroxysms  will  lead  to  the  same  result,  and  I  believe  that 
miscarriage  is  more  apt  to  occur  if  the  malarial  infection  remains  untreated. 
In  pregnant  women  the  drug  should  be  carefully  administered  in  the  smallest 
efficient  dose,  but  it  should  be  administered  if  a  malarial  infection  be  present. 
In  the  event  of  pernicious  symptoms  developing  the  treatment  should  be  the 
same  as  in  any  pernicious  case  of  malaria,  for  the  prospective  mother's  life  is 
endangered,  and  we  are  justified  in  disregarding  that  of  the  child. 

Substitutes  for  Quinine. — The  substitutes  for  quinine  which  have  been 
recommended  from  time  to  time  comprise  preparations  of  the  drug  which  are 
less  toxic  than  the  ordinary  salts,  and  other  drugs  which  have  been  found  to  be 
beneficial  in  the  treatment  of  malaria.  It  may  be  stated  with  truth  that  none 
of  them  are  as  efficient  as  the  salts  of  quinine  and  on  account  of  their  cost,  in 
many  instances,  are  of  very  limited  use  in  practice.  The  following  are  the  more 
important  substitutes,  but  I  have  never  found  it  absolutely  necessary  to  employ 
any  of  them. 

Among  the  other  derivatives  of  cinchona  bark  may  be  mentioned  chincho- 


o 


So       DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 


nine,  chinchonidine,  quinidin,  and  quinoidia,  all  of  which  have  been  used  in  the 
treatment  of  the  malarial  fevers,  but  as  the  symptoms  attending  their  use  are 
similar  to  those  produced  by  quinine  and  as  they  are  very  much  less  efficacious, 
they  have  never  enjoyed  the  confidence  of  the  profession  in  the  treatment  of 
malaria. 

Euchinin,  an  ethyl  carbonate  of  quinine,  is  a  tasteless  preparation,  and 
has  been  extensively  used  in  malaria  by  Nikastro,  Celli,  di  Mattei,  and  Sylvain. 
It  has  to  be  given  in  larger  doses  than  quinine  and  is  apt  to  produce  deafness 
and  derangement  of  vision.  St.  George  Gray  and  Mori  consider  it  a  very 
valuable  addition  to  our  therapeutic  resources  in  the  treatment  of  malaria.  The 
dose  is  a  little  less  than  twice  that  of  quinine.  Personally,  I  have  had  no  ex- 
perience with  this  preparation,  and  it  is  too  costly  for  general  use. 

Salochinin,  or  salicylate  of  quinine,  has  been  recommended  by  some 
writers,  and  Kunst  commends  very  highly  a  preparation  known  as  Aristoclrin 
which  is  administered  in  doses  one-half  as  large  again  as  quinine. 

Methylene  blue  has  been  used  quite  extensively  in  the  treatment  of  ma- 
laria, and  was  first  advocated  by  Guttman  and  Ehrlich,  whose  attention  was 
drawn  to  it  by  the  observations  of  Celli  and  Guarnieri,  who  proved  that  the 
malarial  plasmodia  could  be  stained  by  this  agent  while  still  in  the  circula- 
tion. I  have  used  this  drug  but  seldom  and  have  found  it  unreliable.  In  rare 
instances  it  will  effect  a  cure,  but  it  is  not  to  be  compared  to  the  salts  of  quinine 
in  efficiency.  Marchiafava  and  Bignami  believe  that  this  drug  is  worse  than 
useless,  as  it  may  produce  strangury,  albuminuria,  and  diarrhoea.  When 
administered,  only  the  medicinal  methylene  blue  should  be  used,  and  it  may  be 
given  in  capsules  in  doses  of  0.13  gm.  to  0.2  gm.  (grs.  ii-iii)  every  four  hours. 
It  is  well  to  add  a  little  powdered  nutmeg  to  the  dose  given  as  this  tends  to 
prevent  strangury,  and  warning  should  always  be  given  that  the  urine  will  be 
colored  blue  by  the  drug.  This  drug  has  been  found  efficient  in  tertian  in- 
fections by  Thayer,  Kunst  and  Ivanoff,  but  in  quartan,  and  especially  in  the 
astivo-autumnal  infections  it  has  not  proven  of  much  value.  It  is  always  less 
efficient  than  the  salts  of  quinine. 

Phenocoll. — The  hydrochlorate  of  phenocoll,  a  derivative  of  phenacetin, 
has  been  investigated  by  numerous  observers,  notably  Albertoni,  Pucci,  Novi, 
Anconi,  and  F.  Plehn.  The  general  concensus  of  opinion  is  that,  while  this 
drug  is  sometimes  useful  in  the  mildest  tertian  and  quartan  fevers,  it  cannot  be 
depended  upon  in  the  treatment  of  the  aestivo-autumnal  infections,  and  that  it  is 
not  free  from  injurious  effects,  as  symptoms  of  collapse  have  followed  its  use  in 
therapeutic  doses.  The  dose  is  from  1  to  3  grams  (grs.  xvi  to  lv)  during  the 
24  hours. 

Various  arsenical  preparations  have  been  recommended  as  substitutes 
for  quinine  in  the  treatment  of  acute  malaria,  but  I  have  never  observed  that 
arsenic  had  any  effect  whatever  upon  the  course  of  a  malarial  infection,  and 
I  agree  with  Manson  that  "the  place  for  arsenic  is  not  as  a  substitute  for 
quinine  during  fever,  but  as  a  blood  restorer  after  fever." 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       381 

From  the  summary  given  of  the  substitutes  for  quinine  it  will  be  observed 
that  they  are  comparatively  few  in  number  and  that  all  of  them  have  been  found 
to  be  less  efficient  in  the  treatment  of  malaria.  In  very  rare  instances  it  may  be 
found  necessary  to  employ  one  of  them,  but  I  have  found  that  practically  all 
cases  of  malarial  infection  may  be  treated  by  quinine,  provided  it  is  properly 
administered,  and  I  have  yet  to  see  a  single  case  in  which  quinine,  if  given  early 
enough,  did  not  succeed  in  curing  the  infection. 

General  Treatment  and  Treatment  of  Special  Conditions. 

General  Treatment. — All  malarial  patients  should  be  confined  to  the  bed 
during  the  active  symptoms  of  the  disease,  and  after  the  active  symptoms  have 
subsided  in  the  aestivo-autumnal  cases  it  is  well  to  insist  upon  the  patient 
remaining  in  bed  for  two  or  three  days.  The  bowels  should  be  thoroughly 
evacuated,  preferably  by  a  cathartic  dose  of  calomel  or  of  magnesium  sulphate. 
During  the  acute  stages  symptomatic  treatment  should  be  adopted;  thus  in  the 
cold  stage,  warm  drinks,  with  the  application  of  external  heat  in  some  form,  are 
indicated;  while  in  the  warm  stage,  baths  of  tepid  or  cold  water  or  an  alcohol 
sponge  will  be  found  very  beneficial.  The  ice-pack  or  bath  should  always  be 
used  in  hyperpyrexia.  Antipyretics,  such  as  acetanilide  or  phenacetine,  should 
never  be  used  during  a  paroxysm  of  malarial  fever,  as  they  never  do  any  good 
and  may  do  much  harm.  If  vomiting  be  exhausting,  the  nervous  symptoms 
pronounced,  or  pain  be  excessive,  a  hypodermic  of  morphia  is  allowable,  but 
this  drug  should  not  be  used  if  it  is  possible  to  avoid  it.  Subnormal  tempera- 
ture is  best  combated  by  hot  baths,  strong  coffee,  and  massage,  while  severe 
headache  is  often  greatly  relieved  by  the  ice-cap.  Should  cardiac  weakness  be 
present,  suitable  stimulants  should  be  administered,  the  most  useful  being 
strychnine,  atropine,  and  brandy;  if  the  weakness  is  extreme  these  should  be 
administered  hypodermically.  While  the  treatment  of  special  symptoms  arising 
during  the  malarial  paroxysm  is  of  great  importance,,  it  should  be  remembered 
that  all  other  treatment  is  useless  unless  quinine  be  administered,  so  far  as 
curing  the  infection  is  concerned,  and  that  the  prompt  and  proper  administra- 
tion of  this  drug  will  alone,  in  many  instances,  cause  the  disappearance  of  all 
alarming  symptoms.  It  should  always  be  our  aim  to  administer  quinine  at 
once  in  every  patient  known  to  have  malarial  fever. 

During  the  attack  the  food  should  be  liquid  in  character,  consisting  largely 
of  milk,  broths,  and  thin  gruels.  The  drink  should  be  water  or  lemonade,  the 
latter  especially  being  greatly  relished  by  most  patients,  and  Tomassi-Crudelli 
has  observed  a  marked  improvement  in  cases  in  which  the  juice  of  the  lemon 
was  administered  during  the  attack  and  convalescence.  As  the  active  symp- 
toms abate  the  regular  diet  may  be  gradually  resumed,  and  during  convales- 
cence a  nutritious  diet  is  necessary. 

Convalescence. — The  convalescence  from  malarial  infections  which  have 
been  properly  treated  is  usually  rapid,  except  in  the  severe  aestivo-autumnal 


382       DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 

infections,  when  convalescence  may  be  very  slow.  During  convalescence 
besides  the  administration  of  quinine  in  the  manner  already  described,  the  use 
of  some  form  of  iron  and  of  arsenic  is  advisable,  on  account  of  the  anaemia 
invariably  present.  Bland's  pill  and  Fowler's  solution  are  excellent,  or  other 
well-tried  preparations  of  these  drugs  may  be  used.  The  diet  should  be 
generous  and  nutritious,  sufficient  outdoor  exercise  should  be  insisted  upon, 
and  precautions  taken  to  avoid  reinfection.  In  all  cases,  where  it  is  possible, 
a  change  of  climate  to  a  high,  dry  region,  known  to  be  non-malarious,  should  be 
urged,  as  this  will  do  more  for  the  patient  than  any  other  therapeutic  measure. 
Bitter  tonics  are  often  very  useful  in  stimulating  appetite  and  digestion,  and 
the  use  of  some  good  mineral  water,  laxative  in  action,  is  indicated,  especially 
in  female  patients. 

Treatment  of  Special  Conditions. 

Pernicious  Fevers. — In  all  malarial  infections  presenting  pernicious 
symptoms  our first  thought  must  be  to  get  a  sufficient  dose  of  quinine  into  contact 
with  the  plasmodia  at  once,  and  for  this  reason  the  drug  should  be  administered 
by  the  hypodermic  syringe  in  the  dosage  already  mentioned.  After  this  has 
been  done  the  case  should  be  treated  symptomatically,  but  a  thorough  action 
of  the  bowels  should  be  secured  by  the  use  of  calomel.  If  the  case  be  one  of 
the  bilious  remittent  type  the  vomiting  may  be  stopped  or  allayed  by  an  emetic 
dose  of  ipecac  or  mustard  water  followed  by  large  doses  of  subgallate  or  sub- 
nitrate  of  bismuth;  mustard  plasters  over  the  epigastrium,  the  sucking  of 
cracked  ice,  and  the  hypodermic  injection  of  small  doses  of  morphia  are  often 
efficient  in  allaying  the  vomiting.  Symptoms  of  collapse  should  be  treated  as 
already  described.  In  choleraic  cases  opium  is  indicated  and  the  intravenous 
injection  of  normal  salt  solution.  If  coma  be  present,  the  bladder  and  intestine 
should  be  thoroughly  emptied  and  quinine  administered  intravenously.  Where 
there  is  intense  congestion  of  the  cerebral  vessels  and  acute  delirium,  bleeding 
may  be  performed  with  advantage  in  robust  subjects,  but  this  is  contraindicated 
when  marked  anaemia  is  present.  Hyperpyrexia  should  be  promptly  treated 
by  immersion  in  the  cold  bath  until  the  temperature  is  reduced.  It  is  well 
to  give  always  the  cold  bath  if  the  temperature  by  the  mouth  reaches  1060  F., 
and  to  remove  the  patient  from  the  bath  when  the  temperature  has  been  reduced 
to  1020  F.  or  102. 50  F.  If  the  temperature  begins  to  rise  again  the  bath  should 
be  repeated  if  it  reaches  1040  F.  In  algid  forms  of  pernicious  malaria  injection 
of  salt  solution,  external  heat  applied  by  means  of  hot-water  bottles  and  warm 
blankets,  and  the  free  use  of  alcoholic  stimulants  is  indicated. 

Malarial  Cachexia  (Chronic  Malarial  Infection). — The  treatment 
of  chronic  malarial  poisoning  or  malarial  cachexia  consists  in  the  use  of  those 
drugs  which  build  up  the  blood,  the  employment  of  hygienic  measures,  and 
the  use  of  quinine  in  proper  doses  at  regular  intervals.  It  may  be  stated  with 
truth  that  the  treatment  of  this  condition  is  generally  unsatisfactory  if  the 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       383 

patient  remain  in  the  locality  in  which  he  contracted  his  infection,  or  if  he  live 
in  a  locality  in  which  he  is  continually  exposed  to  reinfection.  While 
various  remedial  measures  may  be  pursued  under  such  conditions,  it  will 
often  be  found  that  little  result  will  follow  unless  a  change  in  climate  be  secured, 
and  thus  we  should  always,  in  such  cases,  counsel  a  change  to  a  high  and  dry, 
non-malarial  region,  and  in  the  case  of  patients  living  in  the  tropics,  a  change  to 
a  temperate  region.  The  chief  drugs  used  in  the  treatment  of  this  condition 
are  arsenic,  iron,  and  quinine. 

Arsenic  is  best  used  in  the  form  of  Fowler's  solution,  commencing  with 
4  drops  after  each  meal,  and  increasing  1  drop  every  three  days,  until  from  12 
to  15  drops  are  taken  three  times  a  day.  If  symptoms  occur  at  anytime 
indicating  that  the  physiological  limit  to  the  use  of  the  drug  has  been  exceeded, 
the  treatment  should  be  interrupted  for  a  few  days,  and  resumed  with  the  same 
dose  which  was  being  taken  just  prior  to  the  occurrence  of  the  unfavorable 
symptoms.  There  can  be  no  doubt  that  arsenic  has  some  effect  upon  the 
Plasmodia  of  malaria,  as  Gautier  has  shown  that  it  produces  fragmentation  of 
the  protoplasm  of  the  gametocytes  and  Durham  claims  that  this  form  of  the 
Plasmodia  is  destroyed  by  the  drug.  From  this  it  would  appear  that  arsenic 
might  be  of  great  value  in  the  prophylaxis  of  malaria,  although  we  have  no  data 
which  indicate  that  it  is  of  much  value  in  this  direction. 

Iron  in  some  form,  such  as  Basham's  mixture  or  the  Blaud  pill,  is  of 
undoubted  value  in  the  treatment  of  malarial  cachexia,  stimulating  the  blood- 
forming  organs  and  thus  repairing  the  damage  done  to  the  blood  by  the  plasmodia. 

Grassi  has  recommended  a  combination  of  quinine,  arsenic,  and  iron, 
known  as  esanophele  in  the  treatment  of  both  acute  and  chronic  malaria 
and  in  malarial  prophylaxis,  claiming  that  better  results  are  obtained  with  this 
mixture  than  with  any  of  the  drugs  when  used  alone.  The  preparation  is 
made  in  the  form  of  pills  or  in  solution.  Schaudinn  used  this  combination  in 
chronic  malaria  showing  recurrences  and  in  latent  infections  with  good  results, 
but  in  aestivo-autumnal  infections  and  in  the  malarial  infections  of  the  tropics, 
better  results  are  obtained  in  the  treatment  of  acute  malarial  attacks  by  the  use 
of  solutions  of  quinine  alone.  In  malarial  cachexia  the  esanophele  pills  are 
very  useful,  especially  in  the  treatment  of  children.  The  formulae  of  the 
esanophele  pill  is  as  follows: 

Quinine  bimuriaticum,  0.1  grm. 

Acid  arsenosum,  0.001  grm. 

Ferrum  citricum,  0.3  grm. 

Ext.  amara,  0.15  grm. 

Each  pill  to  contain  the  above. 

Dosage:  Children,  3  to  6  years,  1  pill  at  6  A.  m.  and  1  pill  at  6  P*  M. 
7  to  14  years,  2  pills  at  6  A.  m.  and  1  pill  at  6  P.  M. 
Adults,      2  pills  at  5  A.  m.,  2  at  8  a.  m.  and  1  at  6  p.  m. 


384      DIAGNOSIS,  PROPHYLAXIS,  AM)  TREATMENT  OF  MALARIAL  FEVERS. 

In  children  from  1  to  two  years  of  age  the  following  solution,  known  as 
Esanophele  Solution  No  1  is  given: 

Each  teaspoonful  contains,  Quin.  bimuriate,  0.12  gm.;  Arsenous  acid 
0.0003  gm.;  Ferrum  citricum,  0.03  gm.;  and  Ext.  amara,  0.1.  A  teaspoonful, 
or  5  c.c,  is  given  at  6  A.  M.,  9  A.  M.  and  12  noon  for  15  days. 

In  children  from  7  to  12  months  of  age,  Esanophele  Solution  No.  2  is 
recommended,  each  teaspoonful  containing;  Quin.  bimuriate,  0.1  gm. ;  Arsenous 
acid,  0.0002  gm.;  Ferrum  citricum,  0.013  gm-;  and  Ext.  amara,  0.1  g.  A 
teaspoonful  is  given  at  7  a.  m.  and  at  10  a.  m.  for  15  days.  I  have  had  no  experi- 
ence with  this  mixture,  but  it  would  appear  from  the  evidence  of  those  who 
have  used  it  that  it  is  valuable  in  the  treatment  of  malarial  cachexia  and  in 
latent  malaria  in  the  inhabitants  of  malarial  localities. 

Warburg's  Tincture  has  been  used  very  extensively  in  the  treatment  of 
chronic  malaria,  but  I  have  never  seen  much  benefit  follow  its  use  in  the  few 
cases  in  which  I  have  employed  it,  although  many  practitioners  in  the  tropics 
consider  it  an  invaluable  mixture  in  the  treatment  of  malaria.  I  believe  that 
where  it  does  do  good  it  is  entirely  due  to  the  quinine  which  it  contains,  and  it  is 
a  well-known  fact  that  the  formula  of  the  original  Warburg's  tincture  has  been 
lost  and  that  the  preparations  in  the  market  are  filled  with  inert  drugs,  pos- 
sessing, so  far  as  we  know,  no  therapeutic  use  whatever.  Some  authors  claim 
that  they  have  seen  this  preparation  succeed  in  curing  malaria  where  quinine 
alone  has  failed,  but  it  is  very  doubtful  if  a  careful  study  of  such  instances  would 
establish  the  truth  of  this  statement.  I  have,  from  personal  experience,  arrived 
at  the  conclusion  that  Warburg's  tincture  is  of  little  use  in  the  treatment  of  acute 
malarial  infections,  but  that  it  may  have  a  place  in  the  treatment  of  chronic 
infections  where  active  symptoms  are  not  present  and  in  the  mild  latent  in- 
fections so  common  among  the  inhabitants  of  malarial  localities. 

Patients  suffering  from  chronic  malarial  infection  should  be  clothed 
warmly,  should  avoid  exposure  to  either  cold  or  heat,  should  live  quietly,  and 
eat  plenty  of  nourishing  food.  The  great  importance  of  a  change  of  climate  has 
already  been  mentioned,  but  such  patients  should  be  very  careful  about  exposing 
themselves  to  cold  winds  or  to  dampness,  as  much  exposure  is  very  apt  to  be 
followed  by  a  recurrence  of  active  symptoms.  In  patients  going  from  the 
tropics  to  a  temperate  locality  it  is  especially  important  that  chilling  be 
avoided  and  that  quinine  be  taken  during  the  sea  voyage  or  land  journey  and 
for  weeks  after  arriving  at  their  destination.  There  is  nothing  more  commonly 
observed  than  acute  attacks  of  malaria  occurring  after  arrival  in  a  temperate 
climate  in  those  who  have  suffered  from  malaria  in  the  tropics  Such  attacks 
could  be  avoided  by  the  daily  administration  of  quinine. 

Treatment  with  the  Roentgen  Rays — The  effect  of  the  A' -rays  upon, 
certain  protozoa  has  been  thoroughly  studied  by  Schaudinn  and  his  results  offer 
no  hope  that  the  treatment  of  malaria  by  this  means  will  ever  result  in  practical 
benefit,  as  the  exposures  are  so  long  as  to  endanger  the  patient.  That  pro- 
longed exposure  to  the  A-ray  will  ultimately  destroy,  or  at  least  so  injure  the 


DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS.       385 

Plasmodia  as  to  render  them  harmless,  has  been  proven,  but  the  method  is  not 
at  present  capable  of  practical  application. 

Serum  Therapy. — That  the  serum  therapy  of  malaria  will  ever  be  of 
practical  utility  is  open  to  very  serious  question,  and  the  results  so  far  obtained 
are  of  more  interest  to  the  bacteriologist  and  protozoologist  than  they  are  to  the 
physician.  A  curative  serum  would  hardly  become  popular,  as  we  possess  in 
quinine  a  specific  for  the  malarial  fevers,  but  a  prophylactic  serum  would  cer- 
tainly be  a  great  boon  to  mankind.  Up  to  the  present,  however,  such  a  serum 
has  not  been  obtained,  and  it  is  very  doubtful  if  it  ever  will  be.  Several  investi- 
gators have  studied  this  phase  of  malarial  therapy,  and  some  of  their  results 
are  deserving  of  mention.  Kuhn,  for  instance,  has  endeavored  to  use  the 
serum  of  horses  immunized  to  the  South  African  horse  sickness  in  the  treatment 
of  malaria.  This  disease,  according  to  Laveran,  is  due  to  a  protozoon,  Babesia 
equi,  and  Kuhn  considers  that  the  horse  sickness  is  similar  to  human  malaria,  is 
produced  by  a  similar  parasite,  and  that  the  serum  of  an  immunized  horse 
should,  therefore,  prove  specific  in  the  treatment  of  human  malaria.  He  and 
Hovorka  tried  this  method  of  treatment  in  13  cases  of  tertian  malaria,  16  cases 
of  quartan,  and  14  cases  of  pernicious  malaria;  in  the  quartan  cases  it  was  use- 
less, but  in  the  tertian  and  pernicious  cases  it  appeared  to  have  a  very  feeble 
curative  action.  These  results  have  not  been  confirmed  and  there  are  so 
many  objections  that  might  be  raised  to  the  technic  of  the  method  practised 
and  the  interpretation  of  the  results  that  we  are  forced  to  conclude  that 
Kuhn's  method  is  of  no  value  in  the  treatment  or  prophylaxis  of  malaria. 

The  investigations  of  Major  J.  H.  Ford,  of  the  Medical  Corps  of  the  U.  S. 
Army,  are  of  interest  in  that  they  suggest  that  further  study  of  this  subject  may 
result  in  a  specific  serum  therapy  for  the  malarial  fevers.  He  endeavored  to 
secure  an  antitoxic  serum  by  inoculating  rabbits,  monkeys,  and  goats  with 
blood  containing  the  plasmodia  of  human  malaria.  His  conclusions  regarding 
his  work  with  Plasmodium  vivax  are  as  follows: 

"From  the  cases  recorded  it  would  appear  that  the  successive  inoculations 
of  monkeys  or  goats  with  blood  containing  Plasmodium  vivax  gives  rise  in  those 
animals  to  an  antitoxin  which,  when  injected  in  adequate  dosage  into  human 
beings,  may  be  followed  by  disappearance  of  the  parasites  from  the  circulation 
and  disappearance  of  the  symptoms  of  malaria.  This  agent  has  no  apparent 
influence  on  infections  caused  by  a  variety  of  the  malarial  parasite  other  than 
that  from  which  it  was  developed." 

In  a  personal  letter  to  the  writer  Ford  states  that  his  further  work  upon 
this  subject  appears  to  indicate  that  an  immunity  to  the  various  species  of 
plasmodia  cannot  be  produced  by  the  use  of  serum  from  the  animals  experi- 
mented with,  but  suggests  that  the  serum  may  prove  of  value  in  the  differentia- 
tion of  species.  While  of  some  value  in  the  treatment  of  malaria,  according  to 
Ford,  the  serum  is  not  as  efficient  as  quinine,  and  therefore  is  of  no  practical 
value  in  the  treatment  of  these  fevers.  Ford's  work  yet  awaits  confirmation, 
and  it  would  appear  that  further  research  in  this  direction  is  needed  before  the 
theory  can  be  accepted  as  proven  that  immunity  to  any  of  the  species  of  human 
25 


386       DIAGNOSIS,  PROPHYLAXIS,  AND  TREATMENT  OF  MALARIAL  FEVERS. 

Plasmodia  can  be  obtained  by  using  the  serum  of  animals  which  have  been 
inoculated  with  them  or  that  in  such  animals  an  antitoxin  develops  which  can 
be  used  in  the  treatment  of  human  malaria.  . 


Literature  upon  the  Treatment  of  the  Malarial  Fevers. 

1867.      Binz.     Ceoitralblatt.  f.  med.  Wiss,  p.  308. 

1S70.      Bixz.      Ueber    die    antipyretische    Wirkung    von    Chinin   und  Alkohol. 

Vircli.  Archiv,  Bd.  xli,  pp.  23-24. 
'S01.      Ehrlich    and    Guttman.      Ueber    die    Wirkung  des   Methylenblau  bei 

Malaria.      Berl.  klin.  Wochenschr.,  No.  39. 
1892.      Golgi.      Action  de  la  quinine  sur  les  parasites  malariques,  etc.      Rendi- 

conte  del  R.  Instituto  Lombardo,  Series  II,  vol.  xxv,  Fasc.  3  and  5. 
1892.      Idem.    Ueber  die  Wirkung  des  Chininsauf  die  Malaria-parasiten.    Deutsch. 

med.  Wochenschr.,  No.  29,  p.  613;  No.  30,  p.  685;  No.  3 1,  p.  707 ;  No.  32, 

p.  729. 
1S94.      Binz.      Unsere   jetzige    Kenntnis   von   der    Malaria    fieberhirtung  durch 

Chinin.      Centralbl.  f.  d.  med.  Wissensch.,  No.  20. 

1895.  Rasch.      Ueber  das  China  und  die   Krankheiten   im   Konigreich   Siam. 
Virchow's  Archiv,  vol.  cxl,  No.  2,  p.  327. 

1896.  Feuchtwanger.      Die  Behandlung  der  Malaria  in  Kindesalter.  Therap. 
Monatsch.,  August,  p.  439. 

1898.      Plehn,  A.      Die  bisher  und  dem  sog.  Euchinin  gemachten  Erfahrungen. 

Arch.  f.  Schiffs-  und  Tropenhyg.,  Bd.  ii,  No.  4,  p.  234. 
1898.      Leukowicz.      Ueber    Phenocoll,     Analgen,     Chinopyrin     und    Euchinin 

als  antimalarische  Mittel.     Wien.  klin.  Wochenschr.,  No.  41. 
1898.      Gray,  St.  George.      Euchinin  in  Malaria.      Brit.   Med.  Jour.,  Feb.   26, 

P-  551- 

1898.  Zieman.      Ueber  Malaria  and  anderer  Blut-parasiten.      Jena. 

1899.  Dock.      Quinine  in  Malaria.      Jour.  Am.  Med.  Assoc,  July  29. 

1900.  Grassi.      Primo  resoconto  sommario  dell'  experimento  contro  la  Malaria 
fatto  nei  Dintorni  di  Pesto.      Revista  Medica,  Anno  viii,  No.  9. 

1900.      Gros.      Paludisme   et    Quin.    Bull   de  la.    Soc.    de   Med.    de   Gand.,    Sep- 
tember. 

1900.  Ivanoff.      Ueber  die   Behandlung  der  Malaria  mit   Methylenblau.      Ge- 
neesh.  Tijdschr.  v.  Nederl.  Indie.,  vol.  xli,  p.  493. 

1 90 1.  Rose,  A.      Methylene  Blue  in  Malarial  Disease.      New  York  Med.  Jour., 
vol.  xi,  No.  9. 

1901.      Kunst,  J.  J.      Die   Behandlung  der  Malaria  mit  Anilinblau.      Deutsch. 

med.  Wochenschr.,  Therap.  Beil.,  No.  5. 
1 90 1.      Atkinson  and  Long.      Methylene  Blue  in  the  Treatment  of  Malignant 

Malarial  Fever.      The  Lancet,  May  16. 
1 90 1.      Kleine.      Ueber  die  Resorption    von  Chininsalzen.      Zeitschr.    f.    Hyg., 

etc.,  Bd.  xxxviii,  No.  3,  p.  458. 
1 90 1        Braddon,   W.  J.      Note   on   the    Rapid  Cure  of   Tropical  Fevers.      Jour. 

Trop.    Med.,  June  1,  p.  185. 
1901.      Bluenchen.      Zur    Technik    und    Verwendbarkeit    subcutaner    Chinin- 

injektionen.      Deutsch.      med.  Wochenschr.,  No.  17. 
1 90 1.      La  Monaco  and  Panichi.      Die  Wirkung  der  antiperiodischen  Heilmit- 

tel    auf    den    Malariaparasiten.      Untersuchungen    zur    Naturlehre    des 

Menschen  and  der  Tiere,  Bd.  xvii,  p.  22. 


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1901.     Gualdi  and  Martirano.      L'azione  della  chinina  sulle  semilune.     An- 

nali  d'lgiene  sperimentale  e  Policlinico. 
1 90 1.      Capogrossi.      Intorno  all'  azione  della  chinina  sui  parasiti  della  malaria. 

II  Policlinico,  December. 
1 90 1.      Kuhn,    P.      Ueber   eine    Impfung   gegen  Malaria.      Arch.   f.  Schiffs-  und 

Tropenhyg.,   Bd.  v,  No.  9,  p.   283. 

1 90 1.  Craig.     The  Aestivo-autumnal  Malarial  Fevers.      New  York. 

1902.  Gautier.  Sur  un  traitement  specifique  tres  puissant  des  fievres  palus- 
tres.  comptes  rend,  hebdomadaires.  II,  Paris. 

1902.  Hovorka.  Ueber  Impfung  gegen  Malaria  mit  dem  Kuhn'schen  Serum 
in  Bosnien.      Wiener  med.  Presse,  No.  71. 

1902.  King,  A.  F.  A.  A  New  Factor  in  the  Etiology  of  Malarial  Fever,  Indi- 
cating New  Methods  of  Treatment.     Am.  Jour.  Med.  Sciences,  Feb. 

1902.  Borrow,  H.  P.  W.  Malaria  Treated  by  the  Hypodermic  Injection  of 
Quinine.      Brit.  Med.  Jour.,  Jan.  25,  p.  201. 

1902.  Kolosvary.  Ueber  die  Wirkung  eines  neuen  geschmacklosen  Chinin- 
praparates,  des  Salochinins,  auf  die  Malaria.  Die  Heilkunde,  Septem- 
ber. 

1903.  Sylvaine.  L'Euchinin  et  sa  valeur  therapeutique.  Arch.  f.  Schiffs- 
u.  Tropenhyg.,  Bd.  vii,  No.  2,  p.  85. 

Nuastro.  Ueber  Euchinin.  Gaz.  med.  Lombardo,  Anno  lxiii,  No.  3. 
Baum,  H.  Das  Aristochinein  Ersatzmittel  des  Chinins.  Die  Heilkunde, 
May. 

Schaudinn,  F.  Ueber  den  Einfluss  der  Rontgenstrahlen  auf  Protozoen. 
Arch.  f.  d.  gesamte  Physiol.,  Bd.  lxxvii. 

Masucci.  L'arrenal  nell'  infezione  malarica.  Annali  di  Med.  Navale, 
ix,  vol.  i,  p.  299. 

Ford,  J.  H.  The  Antitoxin  Treatment  of  Tertain  Malarial  Infections. 
Med.  Record,  vol.  lxvi,  No.  26. 

Mariani.  L'assorbmiento  e  l'eliminazione  della  chinina,  etc.,  Atti  della 
Societa  per  gli  Studi  della  malaria,  p.  211. 

Kunst,  J.  J.      Ueber  die    Behandlung   Malariakranker   mit   Aristochen. 
Archiv.  f.  Schiffs-  und  Tropenhyg.,  Bd.  viii,  No.  3,  p.  126. 
Craig.      The  Malarial  Fevers.      Osier's  "Modern  Medicine,"  vol.  i,  p.  442, 
Philadelphia. 


1903 
1903 

1903 

1903 

1904 

1904 

1904 

1907 


PART  VI. 

HAEMOGLOBINURIC  FEVER. 


HAEMOGLOBINURIC  FEVER. 

Synonyms. — Black-water  fever;  Bilious  remittent  fever;  Bilious  haema- 
turic  fever;  Melanuric  fever;  Haematuric  fever;  Malarial  haematuria;  Haemo- 
globinuria.  German:  Schwarzwasser  fieber.  French:  Fievre  bilieuse  haemo- 
globinurique ;  Fievre  haematurique;  Fievre  malanurique.  Italian:  Febbre 
emoglobinurica. 

Definition. — An  acute  febrile  disease,  occurring  in  tropical  and  subtropical 
regions,  and  characterized  by  fever,  bilious  vomiting,  jaundice,  and  haemo- 
globinuria. 

Believing  as  I  do  that  haemoglobinuric  fever  has  no  etiological  connec- 
tion with  the  malarial  fevers,  it  would  seem  somewhat  out  of  place  to  consider 
this  condition  in  a  work  devoted  to  the  malarial  fevers  and  to  the  protozoa  of 
the  blood,  but  as  the  disease  most  frequently  occurs  in  malarial  regions,  and 
very  often  in  the  subjects  of  malarial  infection,  I  have  thought  it  wise  to  give 
a  concise  description  of  haemoglobinuric  fever,  including  the  most  recent  views 
regarding  its  etiology. 

Like  kala-azar,  this  disease  has  long  been  considered  as  due  to  malarial 
infection,  but  the  more  we  inquire  into  its  etiology,  its  distribution,  symptoma- 
tology, and  pathology,  the  more  must  we  become  convinced  that  the  malarial 
nature  of  the  condition  is  far  from  certain,  and  that  the  evidence  points  to 
its  being  a  separate  disease  entity,  in  all  probability  caused  by  a  hitherto  undis- 
covered organism.  At  the  present  time  the  question  as  to  the  etiology  of  this 
fever  is  still  undecided,  but  I  believe  that  it  is  wise  to  abandon  the  malarial 
hypothesis  and  endeavor  to  study  the  disease  without  being  biased  by  precon- 
ceived ideas  as  to  its  malarial  nature.  There  is  no  more  important  problem 
awaiting  solution  in  tropical  medicine  than  the  etiology  of  haemoglobinuric 
fever. 

Historical. — We  owe  our  first  knowledge  of  haemoglobinuric  fever  to  the 
French  naval  surgeons,  Dutrouleau,  Berenger-Feraud,  Corre,  and  le  Roy 
de  Mericourt,  who  studied  it  in  the  natives  of  Madagascar  and  the  surrounding 
islands,  as  well  as  in  Guinea  and  the  West  Indies.  Their  descriptions  were 
published  during  the  latter  portion  of  the  nineteenth  century,  and  since  then  a 
voluminous  literature  has  accumulated  dealing  with  this  subject.  The  researches 
of  Marchiafava  and  Bignami,  Mannaberg,  Koch,  Stephens  and  Christophers, 
Thayer,  Manson,  the  brothers  Plehn,  and  Cardamantis  have  added  greatly 
to  our  knowledge  within  recent  years,  and  the  disease  is  now  being  studied  by 
numerous  investigators  in  all  parts  of  the  world.  The  first  cases  reported  in 
this  country  were  those  of  Cummings,  in  Louisiana,  in  1859. 

Geographical  Distribution. — The  geographical  distribution  of  haemo- 

391 


392  HAEMOGLOBINURIC    FEVER. 

globinuric  fever  is  very  wide,  and  it  is  an  important  fact,  as  regards  etiology, 
that  this  fever,  while  most  common  in  malarial  localities,  also  occurs  in  regions 
which  are  free  from  malaria,  while  in  many  of  the  most  severely  infected  malarial 
regions  the  disease  does  not  occur  except  in  the  form  of  imported  cases. 

In  North  America  haemoglobinuric  fever  occurs  in  almost  all  of  the 
Southern  States,  having  been  reported  from  Virginia,  North  Carolina,  South 
Carolina,  Georgia,  Florida,  Louisiana,  Texas,  Arkansas,  Mississippi,  Alabama, 
and  Tennessee.  It  is  commonly  observed  in  some  localities  in  most  of  these 
States,  but  has  been  investigated  but  little  as  to  its  frequency  and  mortality. 

In  Central  America  the  fever  occurs  upon  the  Isthmus  of  Panama,  in 
Honduras,  Nicaragua,  Costa  Rica,  and  along  the  entire  coast-line. 

In  South  America  the  disease  occurs  in  Venezuela,  Guiana,  the  Argentine 
Republic,  and  Brazil,  always  along  the  coast-line  and  in  swampy  areas. 

In  the  West  Indies,  black-water  fever  occurs  in  Cuba,  Martinique, 
Guadeloupe,  Trinidad  and  some  of  the  smaller  islands  belonging  to  this  group. 
In  Europe  and  Asia  Minor  the  disease  is  most  prevalent  in  Sardinia, 
Sicily,  and  Greece,  but  it  is  also  found  in  Italy,  Russia,  Turkey,  in  the  Caucasus, 
and  along  the  banks  of  the  Danube.  In  Palestine  it  occurs  in  limited  localities. 
In  India  there  is  good  evidence  for  the  belief  that  the  disease  is  of  recent 
importation,  for  it  is  only  since  1885,  according  to  Manson,  that  it  has  been 
described  as  occurring  in  Hindustan  or  the  East.  At  present  it  has  been  ob- 
served in  the  Madras  Presidency,  in  the  Punjab,  along  the  Ganges,  around 
Bombay,  and  in  Assam  and  Burmah.  The  Malay  Peninsula,  Cochin-China, 
Siam,  and  Southern  China  are  all  infected  with  haemoglobinuric  fever. 

In  the  East  Indies,  haemoglobinuric  fever  has  been  reported  from  Sumatra 
Java,  the  Celebes,  the  Bismarck  Archipelago,  and  New  Guinea.  It  is  very 
rare  in  the  Philippine  Islands,  only  a  few  cases  having  been  reported,  and  it  is 
probable  that  these  were  imported  or  were  suffering  from  a  haemoglobinuria 
induced  by  other  causes. 

In  Africa  this  disease  has  been  most  thoroughly  studied  and  there  it  is 
most  prevalent.  From  the  earliest  explorations  of  that  continent  black-water 
fever  has  been  one  of  the  most  dreaded  foes  of  the  white  man  and  one  of  the 
greatest  obstacles  to  the  opening  up  of  the  country.  It  is  not  found  in  all  parts  of 
Africa,  but  is  especially  deadly  along  the  West  Coast  and  along  the  Congo  and 
the  deltas  of  the  Niger  and  Gambia  rivers.  In  Sierra  Leone,  Cameroon,  Nigeria, 
and  along  the  Gold  Coast  black-water  fever  is  a  veritable  curse.  It  occurs  also 
along  the  East  Coast,  in  British,  German,  and  Portuguese  East  Africa  and  in 
the  Congo  Free  State.  It  occurs  in  British  Central  Africa,  in  Uganda,  the 
Soudan,  and  Algeria.  Egypt  is  free  from  this  disease.  It  occurs  also  in  Mada- 
gascar and  in  Mauritius,  Reunion,  Bourbon,  and  the  Comoro  Islands.  Cases 
have  been  reported  from  Formosa. 

From  this  summary  of  the  geographical  distribution  of  haemoglobinuric 
fever  it  is  evident  that  while  the  disease  does  occur  in  many  regions  in  which  the 
malarial  fevers  are  endemic,  it  also  occurs  in  others  in  which  malaria  is  rare  or 


HAEMOGLOBINURIC    FEVER. 


393 


absent,  and  that  it  does  not  occur  in  many  regions  which  are  intensely  malarial. 
Thus  certain  parts  of  Japan  are  badly  infected  with  malaria,  but  black-water 
fever  has  never  been  reported  as  occurring  there.  In  the  Philippines,  where  I 
served  in  a  most  intensely  infected  region  as  regards  malaria,  I  never  observed 
a  single  case  of  haemoglobinuria,  and  it  may  be  stated  as  a  fact  that  haemoglo- 
binuric  fever  is  so  rare  in  these  islands  as  to  be  a  medical  curiosity,  despite  the 
fact  that  all  forms  of  malaria  are  extremely  common  throughout  the  islands, 
many  of  them  being  of  pernicious  character.  There  is  good  reason  to  doubt, 
indeed,  if  a  single  case  of  genuine  haemoglobinuric  fever  has  ever  been  observed 
in  the  Philippine  Islands. 

Some  authorities  endeavor  to  explain  the  absence  of  haemoglobinuric  fever 
in  malarial  regions  by  claiming  that  it  is  frequent  only  where  there  is  a  large 
amount  of  latent  infection,  but  there  are  many  observations  upon  record  which 
negative  such  a  contention.  '  Thus,  at  Camp  Stotsenburg,  in  the  Philippines, 
the  ratio  of  latent  infection  (or  children  and  adults  showing  plasmodia  in  the 
blood  without  symptoms)  was  very  high,  yet  a  case  of  haemoglobinuric  fever 
has  never  been  observed  in  that  locality. 

The  disease  is  limited,  as  regards  its  endemicity,  to  low-lying  coast-lines, 
and  swampy  regions  situated  near  the  coast.  This,  of  course,  suggests  the 
transmission  of  the  disease  by  mosquitoes,  and  also  its  relation  to  malaria. 

As  regards  seasonal  prevalence,  it  may  be  stated  that  in  the  United  States 
the  disease  is  most  prevalent  in  the  late  summer  and  in  autumn,  while  in 
tropical  regions  it  is  most  prevalent  following  the  end  of  the  rainy  season. 

Epidemics  of  black-water  fever  have  been  reported  by  Masterman,  Wenyon, 
and  Plehn,  but  such  epidemics  are  very  rare,  and  occur  only  when  unsanitary 
conditions,  such  as  overcrowding  and  exposure,  are  present. 

Frequency  of  Occurrence.— On  account  of  the  lack  of  sufficient  data  it 
is  very  difficult  to  arrive  at  a  true  conception  of  the  frequency  of  the  occurrence 
of  haemoglobinuric  fever,  but  it  is  an  undoubted  fact  that  it  is  a  rare  disease 
when  compared  to  the  malarial  fevers,  which,  by  many,  are  considered  to  stand 
in  etiological  relationship  to  it,  for  in  many  regions  in  which  the  malarial  fevers 
are  very  numerous,  black-water  fever  is  unknown  or  is  so  rare  as  to  occasion 
surprise  when  a  case  occurs.  The  following  table,  compiled  from  Deaderick's 
excellent  resume  of  this  fever,  will  serve  to  illustrate  the  frequency  of  this  disease 
as  observed  by  various  authors: 


Observer 

Place                                Time 

No.  of  cases 

Brown    

British  Honduras  .  .  . 

Panama 

Porto  Empedoclo   .  .  . 

India 

Cameroon 

i  year 3 

8  months    20 

1 2  years 17 

Gorgas 

Moscato   

Seal 

Doering 

7  years 

9  months   

6 

40 

394  HAEMOGLOBINURIC    FEVER. 

As  regards  the  relative  frequency  of  the  malarial  fevers  and  haemoglobin- 
uric  fever  in  localities  where  both  occur,  the  following  data  is  of  interest: 
Pampoukis,  in  Greece,  observed  34,937  cases  of  malaria,  of  which  0.7  per  cent, 
presented  haemoglobinuria;  Burot  and  Lagrand,  five  out  of  599  fatal  cases  of 
malaria ;  Ipscher,  in  Cameroon,  observed  285  cases  of  malaria  in  one  year,  and  20 
cases  of  haemoglobinuric  fever;  Sims  saw  over  a  hundred  cases  of  haemoglobin- 
uria in  20  years'  practice  in  the  Congo  region,  but  during  that  time  saw 
thousands  of  case's  of  malaria.  Burot  and  Legrand  saw  31  fatal  cases  of 
haemoglobinuric  fever  in  Senegal  and  the  Soudan  and  155  deaths  from  the 
malarial  fevers,  while  Davidson  states  that  in  Nossi  Be  the  proportion  of  black- 
water  cases  to  malaria  was  as  1  is  to  14. 

The  statistics  given  above  apply  only  to  those  regions  in  which  haemo- 
globinuric fever  is  most  prevalent,  but  if  we  take  those  localities  in  which  the 
malarial  fevers  are  prevalent  and  in  which  black-water  fever  is  rare,  the  relative 
proportion  will  be  very  greatly  reduced.  In  my  own  experience,  covering  10 
years'  observation  of  the  malarial  fevers,  during  which  time  I  have  studied 
nearly  six  thousand  cases  of  malaria,  I  have  observed  haemoglobinuria  but 
once,  and  then  the  condition  was  not  at  all  typical  of  haemoglobinuric  fever. 
All  of  these  cases  were  observed  in  Cuba  or  in  the  Philippines,  or  in  the  United 
States  in  the  persons  of  soldiers  returning  from  those  countries.  When  we  take 
into  consideration  that  most  of  the  patients  were  white  men,  susceptible  to 
haemoglobinuric  fever  and  all  suffering  from  malaria,  I  regard  it  as  evi- 
dent that  haemoglobinuric  fever  is  not  due  to  the  malarial  plasmodia,  but  to 
some  other  cause. 

Predisposing  Causes. — All  ages  and  both  sexes  are  susceptible  to  this 
disease,  but  it  is  said  to  be  most  frequently  observed  in  the  middle  aged,  and  in 
those  debilitated  by  preexisting  disease.  A  previous  attack  of  malaria  is  said 
by  many  authorities  to  be  absolutely  necessary  in  order  that  haemoglobinuric 
fever  develop,  and  some  have  gone  so  far  as  to  claim  that  there  is  no  case  upon 
record  of  the  occurrence  of  this  disease  in  an  individual  who  had  never  suffered 
from  a  malarial  infection.  As  a  matter  of  fact,  there  are  numerous  instances 
of  persons  who  had  never  had  malaria  developing  haemoglobinuric  fever,  and 
Manson1  says:  black- water  fever  frequently  attacks  people  who  previously 
had  never  had  a  single  paroxysm  of  intermittent  fever."  It  is  but  natural  that 
the  two  diseases  should  occur  in  the  same  individual  frequently,  in  regions  in 
which  both  are  endemic. 

Length  of  residence  appears  to  have  an  important  influence  upon  the  liability 
to  haemoglobinuric  fever  in  many  instances,  but  that  a  long  residence  in  the 
infected  locality  is  unnecessary  is  shown  by  the  experience  of  such  observers 
as  Plehn,  Ritchie,  Cardamantis,  Daniels,  and  Lynch  and  Scott,  who  all  report 
instances  of  perfectly  healthy  individuals  being  attacked  within  two  to  three 
months  after  reaching  the  infected  territory,  and  before  there  was  any  evidence 


1  Tropical  Diseases,  4th  Ed.,  London. 


HAEMOGLOBINURIC    FEVER.  395 

of  a  malarial  infection.  Manson  states  that  he  has  been  frequently  informed 
by  officers  of  the  African  colonial  service  that  they  were  suddenly  attacked  by 
black-water  fever  while  in  perfect  health,  and  Daniels  states  that  a  malarial 
history  is  denied  by  a  goodly  proportion  of  the  sufferers  from  black  water  unless 
they  have  resided  for  over  a  year  in  the  infected  region. 

As  regards  race,  haemoglobinuric  fever  chiefly  attacks  the  whites,  but  the 
negro  is  not  immune  as  a  race.  In  localities  in  which  the  fever  is  endemic 
the  negro,  if  present,  undoubtedly  develops  an  immunity  against  the  disease, 
but  numerous  observers  have  seen  instances  of  infection  in  negroes.  F.  Plehn 
reports  an  epidemic  occurring  among  the  negroes  in  the  Cameroon,  and  it 
has  been  repeatedly  observed  that  negroes  introduced  into  an  infected  region 
from  an  uninfected  one,  are  susceptible  to  the  disease.  Chinese  are  said  to  be 
almost  as  susceptible  as  the  white  man,  but  Daniels  claims  that  the  native  of 
India  is  only  one-fourth  as  susceptible  as  is  the  European. 

Change  of  Residence  is  often  followed  by  a  recurrence  of  haemoglobinuria 
in  those  who  have  suffered  from  the  disease,  or  may  be  the  exciting  cause  of 
the  primary  attack,  especially  if  the  change  be  an  abrupt  one  as  regards  climate 
or  altitude.  Recurrences  are  frequently  observed  and  are  generally  brought 
about  by  exposure,  change  of  climate,  or  removal  from  a  low  to  a  high  altitude. 
Patients  returning  from  the  tropics  to  England  or  America  sometimes  develop 
haemoglobinuria  after  arrival. 

Among  the  other  predisposing  causes  of  an  attack  of  haemoglobinuric 
fever  may  be  mentioned  exposure  and  fatigue,  traumatism,  excessive  venery, 
and  alcoholic  excesses.  Haig  believes  that  the  uric  acid  diathesis  strongly 
predisposes  to  haemoglobinuria,  but  there  is  no  experimental  evidence  favor- 
ing his  view. 

Etiology. — The  cause  of  haemoglobinuric  fever  is  unknown,  but  there  are 
three  chief  hypotheses  regarding  its  etiology,  each  supported  by  some  evidence 
of  value,  and  each  ardently  believed  in  by  its  advocates.  These  are:  that 
it  is  due  to  malarial  infection;  that  it  is  due  to  quinine;  and  that  it  is  a  specific 
disease.  All  of  these  theories  have  been  investigated,  and  the  advocates  of 
all  are  able  to  point  to  evidence  favoring  their  claims,  but  I  believe  that  a 
careful  study  of  this  vexed  question  by  an  unprejudiced  observer  must  result 
in  the  conviction  that  the  specific  theory  of  the  etiology  of  the  disease  is  correct, 
and  that  haemoglobinuric  fever  is  a  disease  sui  generis,  caused  by  a  hitherto 
undiscovered  organism,  probably  of  protozoal  nature. 

The  Malarial  Theory. — This  theory  of  the  causation  of  the  fever  is  sup- 
ported by  many  eminent  students  of  malaria,  notably  by  Stephens,  Plehn,  and 
Mannaberg.  The  advocates  of  this  theory  claim  that  the  distribution  of  the 
disease;  the  presence  in  a  large  proportion  of  the  cases  of  malarial  plasmodia; 
the  fact  that  in  most  cases  a  previous  history  of  malarial  infection  can  be  obtained ; 
the  blood  findings  apart  from  the  plasmodia,  and  the  fact  that  the  disease  affects 
those  who  have  resided  for  some  time  in  the  infected  region,  all  point  to  its 
malarial  origin.     It  is  well  to  consider  each  of  these  points  separately  and  by 


39^  HAEMOGLOBINURIC    FEVER. 

so  doing  I  believe  that  the  conclusion  will  be  that  not  one  of  them  can  be 
considered  as  proving  that  black-water  fever  is  malarial  in  origin. 

The  distribution  of  the  disease  I  have  already  referred  to  and  have  shown 
that  in  many  malarial  regions  haemoglobinuric  fever  is  unknown,  although 
these  regions  are  badly  infected  with  the  most  severe  forms  of  malaria,  such 
as  the  aestivo-autumnal.  In  the  Philippines,  where  pernicious  cases  of 
malaria  are  not  uncommon  and  where  the  mortality  from  malaria  in  1902, 
according  to  the  census  of  the  Philippines  Islands,  was  26.8  per  cent,  of  all 
deaths,  there  being  during  that  year  118,476,  deaths  from  these  fevers,  or  17  per 
thousand,  not  a  single  death  is  reported  from  haemoglobinuric  fever,  and  this 
is  true  of  many  other  malarial  localities.  The  fact  that  black-water  fever  has 
been  reported  from  regions  in  which  malaria  is  unknown  also  serves  to  show 
how  little  we  can  depend  upon  the  distribution  of  a  disease  in  considering  its 
etiology.  Many  other  acute  infectious  diseases  are  most  common  in  regions 
infected  with  malaria,  but  because  this  is  so  we  do  not  at  once  conclude  that  they 
must  therefore  be  due  to  malarial  poisoning. 

The  presence  of  malarial  Plasmodia  in  the  blood  of  a  large  proportion  of 
patients  suffering  from  haemoglobinuric  fever  is  considered  by  many  as  proving 
its  malarial  origin,  but  many  other  conditions  occur  in  malarial  regions  which 
no  one  would  consider  for  a  moment  as  being  due  to  malaria,  but  in  which 
malarial  plasmodia  are  found  in  the  blood. 

It  is  but  natural  that,  in  an  intensely  malarial  district,  patients  suffering 
from  haemoglobinuric  fever  should  present  plasmodia  in  their  blood,  and  the 
fact  that  the  latter  fever  is  most  prevalent  in  malarial  districts  does  not  prove 
that  it  is  due  to  malaria,  but  that  it  depends  for  its  spread  upon  factors  which 
also  favor  the  transmission  of  the  malarial  fevers.  As  regards  the  frequency  of  the 
occurrence  of  malarial  plasmodia  in  the  peripheral  blood  of  black-water  fever 
patients,  I  have  collected  273  cases  reported  in  the  literature,  of  which  109,  or 
nearly  40  per  cent,  showed  malarial  plasmodia  in  the  blood.  Stephens  and 
Christophers  and  Mannaberg  have  shown  that  the  number  of  plasmodia  in  the 
blood  varies  with  the  time  of  examination,  95  per  cent,  of  patients  showing  them 
the  day  before  the  attack,  60  to  70  per  cent,  showing  them  the  day  of  the  attack, 
and  17  to  20  per  cent,  showing  them  the  day  after  the  attack.  This  fact  has 
been  used  in  the  endeavor  to  discount  the  proofs  of  the  absence  of  plasmodia  in 
haemoglobinuric  fever,  but  there  are  scores  of  cases  upon  record  in  which  the 
blood  was  examined  both  before,  during,  and  after  the  attack,  and  no  plasmodia 
were  ever  found.  If  the  fever  is  due  to  the  presence  of  plasmodia,  why  is  it 
that  in  case  after  case  these  organisms  are  not  found  though  repeated  and  careful 
search  is  made  for  them,  the  spleen  having  been  punctured  in  some  cases  with 
a  negative  result? 

It  appears  to  me  most  illogical  to  claim,  that  because  a  large  proportion  of 
patients  suffering  from  haemoglobinuric  fever  show  malarial  plasmodia  in  their 
blood,  the  disease  must  necessarily  be  due  to  them.  Take,  for  example, 
infection  with  ankylostoma.     This  parasite  is  most  common  also  in  malarial 


HAEMOGLOBIN  URIC    FEVER.  397 

regions,  because  such  regions  are  most  favorable  to  its  development.  It  also 
will  be  found  present  in  a  vast  majority  of  patients  suffering  from  malaria  in 
such  regions,  yet  we  do  not  for  a  moment  believe  that  ankylostomiasis  must 
therefore  be  due  to  malaria,  for  in  this  instance  we  have  demonstrated  that  it  is 
due  to  a  definite  parasite.  In  haemoglobinuric  fever,  unfortunately,  the 
parasite  has  not  been  discovered,  and  so  it  is  easier  to  consider  it  of  malarial 
origin,  because  the  two  diseases  frequently  coexist.  In  India  for  years  kala- 
azar  was  considered  of  malarial  origin,  and  it  was  not  until  the  discovery  of 
Leishmania-donovani  that  this  notion  was  abandoned.  Such  an  experience 
should  serve  as  a  warning  to  us  in  our  conceptions  of  the  etiology  of  haemo- 
globinuric fever. 

A  previous  history  of  malarial  infection  is  undoubtedly  to  be  obtained  in 
most  of  our  cases  of  haemoglobinuric  fever'  but  here  again  the  reason  is  not  far 
to  seek.  The  occurrence  of  the  disease  most  frequently  in  malarial  localities 
makes  it  inevitable  that  most  patients  suffering  from  it  should  have  previously 
suffered  from  malaria  or  may  be  suffering  from  that  infection  at  the  time  they 
develop  haemoglobinuria.  From  what  we  know  of  black-water  fever  it  is 
evident  that,  compared  with  malaria,  it  is  a  rare  disease,  and  it  therefore  happens 
that  most  patients  residing  long  enough  in  a  locality  to  develop  black-water 
fever  have  already  suffered  from  malaria.  It  has  been  asserted  by  the  most 
ardent  advocates  of  the  malarial  origin  of  haemoglobinuric  fever  that  not  a 
single  case  is  on  record  of  the  outbreak  of  this  disease  in  a  patient  who  had  not 
previously  suffered  from  malaria,  but  such  an  assertion  can  only  be  made  by 
one  who  is  little  acquainted  with  the  literature,  for  numerous  cases  are  reported 
in  which  haemoglobinuric  fever  developed  in  perfectly  healthy  individuals 
within  two  or  three  months  after  reaching  the  infected  locality  and  in  whom 
there  had  never  been  any  symptoms  of  malaria.  Such  cases  have  been  reported 
by  Manson,  Cardamantis,  Plehn,  Ritchie,  Daniels,  and  many  other  observers. 

The  blood  examination  in  cases  of  haemoglobinuric  fever  generally  demon- 
strates an  increase  in  the  large  mononuclear  leucocytes,  and  frequently  the 
presence  of  pigmented  mononuclear  cells.  This  fact  has  been  used  as  a  weighty 
argument  by  the  believers  in  the  malarial  origin  of  the  fever,  as  similar  results 
are  found  in  malaria.  However,  it  is  of  little  real  value  as  an  argument,  for  a 
large  mononuclear  increase  is  observed  in  several  other  diseases  due  to  the 
protozoa,  as  kala-azar  and  trypanosomiasis,  while  the  pigmented  leucocytes 
are  present  in  patients  who  have  suffered  from  malaria,  even  after  symptoms  of 
infection  have  been  absent  for  weeks.  While  the  presence  of  pigmented 
leucocytes  may  indicate  that  at  some  time  the  patient  has  suffered  from 
malarial  infection,  it  certainly  is  very  poor  proof  that  an  attack  of  haemo- 
globinuric fever  is  due  to  malaria. 

The  relation  of  long  residence  in  an  infected  locality  to  the  malarial  origin  of 
the  fever  has  already  been  mentioned.  It  is  sufficient  to  repeat  that  while 
most  cases  occur  only  after  the  first  twelve  months  of  residence,  many  have  been 
reported  in  which  the  disease  appeared  within  two  to  three  months  after  enter- 


398  HAEMOGLOBIN  URIC    FEVER. 

ing  the  infected  territory  and  in  perfectly  healthy  individuals,  thus  proving 
that  long  residence  is  not  essential  to  the  development  of  the  disease.  That 
most  of  the  cases  develop  after  a  residence  of  a  year  or  more  would  appear  to 
indicate  that  the  disease  is  one  of  long  incubation  or,  and  this  is  more  probable, 
due  to  an  organism  which  is  seldom  met  with  or  which  requires  certain  peculiar 
conditions  favorable  for  its  development  before  infection  occurs.  Recently  a 
number  of  authors  have  claimed  that  while  the  plasmodia  of  malaria  have  no 
direct  etiological  relationship  to  haemoglobinuric  fever,  malarial  infection  is, 
nevertheless,  a  necessary  predisposing  cause,  bringing  about  certain  conditions 
in  the  blood  and  tissues  necessary  for  the  existence  of  the  parasite  causing  the 
fever.  While  these  theories  are  interesting,  they  simply  beg  the  question,  and 
1  believe  are  of  little  value  as  working  hypotheses,  for,  as  shown,  haemoglobin- 
uric  fever  does  occur  where  there  has  been  no  malarial  infection,  and,  there- 
fore, we  are  justified  in  believing  that  it  is  not  caused  by  the  malarial  plasmodia 
or  dependent  upon  the  changes  produced  in  man  by  infection  with  these 
parasites. 

The  Quinine  Theory. — Many  observers,  while  denying  that  malaria  is 
responsible  for  the  appearance  of  haemoglobinuria,  believe  that  this  fever  is 
produced  in  certain  susceptible  individuals  by  the  administration  of  quinine. 
In  1858,  Veratas,  a  Greek  physician,  suggested  this  explanation  of  the  occur- 
rence of  haemoglobinuria,  and  in  1874,  Tomaselli,  of  Italy,  reported  in  favor 
of  this  theory,  and  it  has  since  been  accepted  by  many  practitioners  in  malarial 
localities.  When  Koch  gave  it  the  support  of  his  great  authority,  the  scientific 
world  believed  that  at  last  the  etiology  of  the  disease  was  explained,  but  even 
Koch  does  not  state  that  quinine  is  the  sole  cause  of  the  fever.  As  a  matter  of 
fact,  many  cases  of  black-water  fever  have  been  reported  in  which  no  quinine  had 
been  taken  previously  to  the  attack,  and  Cardamantis  has  reported  no  less 
than  32  cases  in  Europeans  who  had  never  taken  a  dose  of  quinine.  It  is  true, 
however,  that  very  rarely  the  administration  of  quinine  has  been  followed  by 
the  appearance  of  haemoglobinuria,  but  it  is  very  doubtful  if  the  symptoms, 
beyond  the  occurrence  of  blood  in  the  urine,  were  those  of  black-water  fever.  I 
have  seen  two  cases  in  which  quinine  caused  haemoglobinuria,  even  when  given 
in  small  doses,  but  there  were  no  symptoms  in  the  least  suggestive  of  haemoglo- 
binuric fever.  That  quinine  has  been  administered  in  most  cases  of  haemoglo- 
binuric fever  prior  to  the  outbreak  of  the  disease  is  due  to  the  fact  that  as  the 
disease  occurs  so  frequently  in  malarial  localities  the  drug  has  been  given  to 
combat  malarial  infection.  It  is  certainly  illogical  to  claim,  because  quinine 
has  been  administered  to  a  patient  suffering  from  malaria  and  who  afterward 
develops  haemoglobinuric  fever,  that  the  drug  is  the  cause  of  the  disease. 
In  many  regions  quinine  is  given  as  a  prophylactic  to  practically  the  whole 
population,  but  because  this  is  so  must  we  believe  that  the  cases  of  black-water 
fever  which  may  occur  are  due  to  this  drug  ?  How  can  we  explain  upon  such  a 
hypothesis  the  absence  of  haemoglobinuric  fever  in  regions  such  as  the  Philip- 
pine Islands,  where  malaria  is  common  and  quinine  is  given  very  extensively  ? 


HAEMOGLOBINURIC    FEVER.  399 

If  we  take  into  consideration  also  that  quinine  is  given  in  many  other  in- 
fections without  producing  haemoglobinuric  fever;  that  it  is  used  with  good 
results  in  the  treatment  of  the  disease  itself,  when  a  malarial  complication  is 
present;  that  there  exists  no  relation  between  the  amount  of  the  quinine  given 
and  the  severity  of  the  disease;  and  that  even  in  those  who  have  suffered  from 
an  attack  of  the  fever  apparently  produced  by  quinine,  the  use  of  the  drug 
afterward  is  harmless;  I  believe  that  we  must  admit  that  quinine  is  not  the 
cause  of  black-water  fever. 

The  Specific  Theory. — Recently  the  theory  that  haemoglobinuric  fever  is 
a  distinct  disease,  produced  by  a  specific  parasite,  probably  protozoal  in  nature, 
has  been  gaining  ground,  and  I  believe  that  ultimately  this  theory  will  be  found 
correct.  The  most  ardent  advocates  of  the  specific  nature  of  the  disease  are 
Manson,  Sambon,  Rho,  and  Blanchard,  while  numerous  other  investigators 
believe  that  only  by  admitting  the  specific  nature  of  the  disease  can  we  explain 
the  apparent  contradictions  inherent  in  the  other  theories.  Manson1  says: 
"I  have  long  entertained  the  idea  that  too  much  has  been  taken  for  granted  in 
relegating  black-water  fever  to  malaria,  and  thereby  ignoring  its  possible 
individuality  as  a  separate  disease;  an  individuality  strongly  suggested  not 
only  by  the  symptomatology,  but  also  by  epidemiology  and  analogy."  The 
resemblance  of  the  disease  to  paroxysmal  haemoglobinuria  and  the  occurrence 
of  a  somewhat  similar  disease  in  cattle,  known  as  Texas  fever,  forcibly  suggests 
that  haemoglobinuric  fever  is  a  distinct  disease,  and  that  it  may  be  due  to  a 
protozoon  closely  allied  to  the  parasite  of  Texas  fever,  Babesia  bigemina.  The 
discovery  of  other  parasites  in  animals  belonging  to  this  genus,  some  of  them 
very  small,  is  of  importance  in  the  consideration  of  this  disease,  for  it  is  not  at  all 
improbable  that  black-water  fever  may  be  due  to  a  babesia  or  allied  organism 
so  small  as  to  escape  our  present  microscopic  lenses,  or  it  may  prove  to  be 
actually  ultramicroscopic  in  size.  Certain  it  is  that  the  distribution  of  the 
disease,  its  epidemiology  and  symptomatology,  and  its  resemblance  to  other 
protozoal  diseases,  would  appear  to  justify  us  in  regarding  it  as  probably 
due  to  a  protozoon,  and  in  view  of  the  fact  that  neither  the  malarial  theory 
nor  the  theory  that  the  disease  is  due  to  quinine  has  been  proven,  that  it  is  wise 
to  consider  the  etiology  of  this  disease  as  still  unsolved. 

Pathology. — The  pathology  of  haemoglobinuric  fever  is  but  little  char- 
acteristic, if  we  do  not  take  into  consideration  the  condition  of  the  urine.  The 
principal  changes  are  found  in  the  kidneys,  blood  and  urine,  the  other  organs, 
save  for  the  changes  brought  about  by  preexistent  or  existing  malarial  infection, 
showing  little  change  of  importance. 

The  Kidneys. — The  kidneys  are  always  congested  and  present  the  evi- 
dences of  acute  venous  congestion  or  acute  nephritis.  The  capsule  is  not 
adherent,  the  cortex  is  thickened,  the  intertubular  capillaries  much  congested, 
and  the  general  appearance  of  the  section  that  of  an  acute  tubular  nephritis. 
Microscopical  examination  shows  marked  epithelial  desquamation  in  the 
1  Ibid. 


400  HAEMOGLOBINURIC' FEVER. 

tubules,  congested  Malpighian  tufts,  and  congested  capillaries.  If  the  patient 
dies  after  three  or  four  weeks  the  kidneys  present  the  lesions  of  a  subacute 
parenchymatous  nephritis.  In  instances  where  a  malarial  infection  compli- 
cates the  haemoglobinuria,  the  sections  of  the  kidneys  may  show  melanin  within 
the  capillaries  or  enclosed  within  the  cells.  In  almost  every  instance  the  cells 
within  the  tubules  contain  a  considerable  amount  of  yellow  pigment,  derived 
from  the  broken-down  red  corpuscles. 

The  Spleen.— Except  in  patients  who  have  suffered  from  malarial  infection 
few  pathological  lesions  are  observed  in  the  spleen  in  fatal  cases,  beyond  en- 
largement, congestion,  and  decrease  in  consistency.  In  fact  the  spleen  is  that 
usually  observed  in  acute  infectious  fevers,  and  does  not  contain  malarial 
pigment  unless  preexistent  malarial  infection  has  occurred.  A  large 
amount  of  yellow  pigment  is  generally  present,  due  to  the  destruction  of  the 
red  cells. 

The  Liver. — The  liver  is  enlarged,  decreased  in  consistence,  and  usually  of 
a  yellowish  color.  Sections  show  albuminoid  degeneration  of  the  liver  cells, 
and  haemosiderin  is  common  in  the  degenerated  cells.  There  may  be  marked 
congestion  of  the  capillaries,  and  it  is  not  uncommon  to  observe  areas  of  focal 
necrosis  in  the  region  of  the  intralobular  vein.  Melanin  is  not  present  except  in 
patients  suffering  from  coincident  malarial  infection. 

The  Brain. — The  brain  shows  no  pathological  lesions  which  are  character- 
istic, and  only  in  patients  having  a  coincident  malarial  infection  is  pigment  or 
parasites  observed  in  this  organ.  The  total  absence  of  pigment  in  the  brain  in 
many  fatal  cases  of  black-water  fever  is  very  suggestive  of  the  lack  of  relation  of 
malaria  to  this  fever,  for  in  almost  every  fatal  case  of  malaria  it  is  not  difficult 
to  demonstrate  plasmodia,  and  especially  pigment,  in  the  capillaries  of  the 
brain. 

Bone-Marrow. — No  changes  of  importance  occur  in  the  bone-marrow. 
If  malarial  infection  is  present  or  the  patient  has  suffered  from  repeated  attacks 
of  malaria,  the  changes  are  those  observed  in  that  disease  which  have  already 
been  described. 

The  Blood. — The  blood  looks  yellowish  or  yellowish-red  in  color,  and  is 
less  viscid  than  normal.  Haemoglobinaemia  or  cholaemia  may  be  present,  but 
in  many  cases  haemoglobinaemia  is  not  present.  Microscopically  the  blood- 
cells  appear  normal  in  size  and  shape,  but  are  generally  paler  than  normal. 
The  presence  of  malarial  plasmodia  in  the  blood  of  haemoglobinuric  fever  has 
already  been  discussed,  and  it  may  be  stated  that  in  many  cases  they  are  not 
present  at  any  time  during  the  disease  or  preceding  it,  and  that  when  they  are 
present  it  simply  means  a  coincident  malarial  infection.  Neither  is  melanin 
present  in  the  blood  in  uncomplicated  cases  of  haemoglobinuric  fever.  During 
the  early  symptoms  of  the  fever  there  may  be  a  marked  leucocytosis,  but  later 
in  the  disease  the  polynuclear  cells  are  decreased,  and  there  is  a  marked  in- 
crease in  the  large  mononuclear  leucocytes,  a  fact  on  which  great  stress  is  laid 
by  the  advocates  of  the  malarial  nature  of  the  disease.     As  we  have  shown, 


HAEMOGLOBINURIC    FEVER.  4OI 

this  mononuclear  increase  is  present  in  other  protozoal  diseases,  and  therefore 
cannot  be  considered  as  characteristic  of  black-water  fever. 

The  Urine. — The  color  of  the  urine  is  usually  a  dark  cherry  red,  but  it  is 
sometimes  necessary  to  use  the  spectroscope  to  detect  the  presence  of  haemoglo- 
bin ;  in  such  instances  the  color  is  a  light  brownish-yellow.  The  reaction  is  alka- 
line, the  specific  gravity  low,  and  there  is  generally  a  large  amount  of  sediment, 
which,  upon  being  examined,  is  found  to  consist  of  yellowish  granular  matter, 
numerous  hyaline  and  haemoglobin  casts,  and  a  very  few  red  blood-corpuscles. 
The  granular  material  is  evidently  composed  mostly  of  the  detritus  of  degen- 
erated red  blood-corpuscles,  and  as  haematuria  is  not  a  characteristic  of  the 
disease,  this  explains  the  very  few  red  corpuscles  which  are  present  in  the  urine. 
Crystals  of  haemotoidin  occur  in  sparse  numbers  in  the  sediment.  The  bile- 
pigments,  may  be  present ;  but  are  not  commonly  observed.  Albumin  is 
always  present  in  large  amount,  mostly  in  the  form  of  serum-globulin,  which  is 
derived  from  the  blood.  The  spectroscopic  examination  of  the  urine  shows 
the  characteristic  spectrum  of  oxyhaemoglobin  and,  in  some  instances,  of 
methaemoglobin. 

Period  of  Incubation. — The  period  of  incubation  in  haemoglobinuric 
fever  is  unknown.  From  the  observations  of  Scott,  in  Africa,  it  would  appear 
that  the  fever  may  occur  after  a  period  of  eight  days  from  exposure  in  the 
infected  territory,  but  it  is  probable  that  the  period  of  incubation  is  a  very 
variable  one,  for  we  know  that  recurrences  take  place  at  long  intervals,  even  of 
months.  Manson  mentions  cases  in  which  the  disease  appeared  for  the  first 
time  in  Europeans  who  had  been  absent  from  the  infected  localities  for  months, 
so  that  it  would  appear  that,  as  in  the  malarial  fevers,  black-water  fever  has  a 
very  uncertain  period  of  incubation. 

Symptomatology. — In  almost  every  case  the  disease  begins  suddenly  with 
a  chill,  after  which  the  temperature  rises  rapidly  to  1030  F.  or  higher.  The 
chill  is  generally  severe,  but  may  be  so  slight  as  to  be  hardly  noticeable.  The 
usual  symptoms  of  fever  are  present,  such  as  malaise,  pain  in  the  muscles  and 
articulations,  loss  of  appetite,  and  mental  depression.  Later  in  the  attack  the 
pain  is  more  severe  in  the  lumbar  region  and  over  the  liver  and  spleen,  while 
in  many  instances  severe  bladder  pain  is  complained  of.  After  the  symptoms 
are  well  pronounced  there  is  marked  desire  to  pass  the  urine  which  presents 
the  characteristic  brownish-red  color  of  "black-water."  The  fever  may  be 
intermittent,  remittent,  or  almost  continuous  in  type,  and  jaundice  slowly 
develops  in  many  instances.  Tympanites  is  a  common  symptom  and  pain 
over  the  stomach  is  often  elicited  upon  pressure.  In  favorable  attacks  there 
is  bilious  vomiting,  but  it  is  not  so  excessive  and  so  long  continued  as  it  is  in 
cases  which  go  on  to  a  fatal  termination.  In  not  a  few  instances  bilious  vomit- 
ing is  absent,  so  that  this  symptom  cannot  be  said  to  be  characteristic  of 
haemoglobinuric  fever.  The  termination  of  the  attack  in  patients  who  recover 
is  usually  by  crisis,  the  temperature  receding,  accompanied  by  profuse  perspira- 
tion, while  the  haemoglobinuria  disappears.  Great  prostration  is  often  observed 
26 


402  HAEMOGLOBINURIC    FEVER. 

after  an  attack  of  haemoglobinuric  fever,  and  convalescence  may  be  much 
delayed  by  recurrences  of  the  haemoglobinuria  and  fever  or  by  the  recurrence 
of  the  fever  alone.  The  haemoglobinuria  may  last  only  for  an  hour  or  two  in 
mild  cases  or  may  persist  at  intervals  for  weeks.  As  the  haemoglobinuria 
disappears,  the  urine,  which  may  have  been  greatly  decreased  in  quantity  at 
the  height  of  the  attack,  becomes  lighter  in  color,  greater  in  quantity,  and  is 
passed  with  less  discomfort  to  the  patient.  The  acute  attack  may  last  only 
a  day  or  may  be  prolonged  over  several  days.  Diarrhoea  is  common,  but 
constipation  is  frequently  observed. 

In  fatal  cases  the  temperature  may  go  to  1040  F.  or  higher;  there  is  severe 
and  prolonged  bilious  vomiting;  bilious  diarrhoea;  great  pain  in  the  loins  and 
the  epigastric  region;  and  a  gradually  developing  somnolence  which  deepens 
into  a  fatal  coma.  In  some  instances  the  symptoms  are  those  of  uraemia, 
due  to  total  suppression  of  the  urine  or  to  the  development  of  nephritis,  while  in 
others  the  fatal  symptoms  are  those  of  severe  haemorrhage,  or  death  may 
occur  from  hyperpyrexia  or  the  typhoid  state  may  develop.  A  marked  decrease 
in  the  total  quantity  of  urine  passed  in  twenty-four  hours  is  always  an  un- 
favorable symptom. 

The  following  clinical  facts  are  of  importance  in  the  symptomatology  of 
haemoglobinuric  fever;  the  temperature  is  not  in  any  way  characteristic  of  the 
disease;  haemoglobinuria  is  constant,  but  unless  accompanied  by  the  other 
symptoms,  such  as  fever,  vomiting,  and  jaundice,  cannot  be  considered  as 
peculiar  to  this  disease;  the  vomiting  of  bile-stained  material  is  so  commonly 
observed  as  to  be  an  important  confirmatory  symptom,  but  alone  is  of  no  value; 
the  microscopic  character  of  the  sediment  in  haemoglobinuric  fever  is  not 
characteristic,  as  the  same  elements  are  found  in  haemoglobinuria  due  to  other 
causes;  the  development  and  persistence  of  jaundice  is  very  characteristic 
when  accompanied  by  other  symptoms. 

The  physical  signs  during  an  attack  of  haemoglobinuric  fever  consist  in 
an  enlargement  of  the  spleen  and  liver  and  a  jaundiced  condition  of  the  sclerae 
and  skin.  A  systolic  murmur  is  not  infrequently  heard,  haemic  in  character, 
and  not  transmitted.  A  bronchitis  may  be  present  or  there  may  be  evidence  of 
congestion  and  oedema  of  the  lungs.  Anaemia  is  generally  marked  when  the 
blood  count  is  made  during  the  attack,  but  counts  made  after  the  symptoms 
have  disappeared  do  not  show  as  severe  a  degree  of  anaemia  as  one  would 
expect  from  the  obvious  destruction  of  the  red  cells. 

In  malarial  localities  an  attack  of  haemoglobinuric  fever  is  often  compli- 
cated by  a  coincident  attack  of  malaria,  and  it  is  certain  that  many  of  the  symp- 
toms of  black-water  fever,  which  have  become  almost  classic  in  our  text-books 
upon  the  subject,  were  in  reality  those  of  malaria,  and  it  is  very  probable  that  a 
more  careful  study  of  our  cases  will  result  in  proving  that  haemoglobinuric 
fever  has  a  definite  and  characteristic  symptomatology  which  will  enable  us  to 
recognize  it  as  having  no  connection  with  the  malarial  fevers  and  peculiar  unto 
itself.     At  the  present  time  the  subject,  both  from  an  aetiological  and  clinical 


HAEMOGLOBINURIC    FEVER.  403 

standpoint,  is  in  a  far  from  satisfactory  condition  and  is  one  of  the  most 
important  of  all  tropical  problems  in  medicine. 

Complications  and  Sequelae. — These  are  few  in  number,  nephritis 
being  the  most  common  of  the  sequelae,  and  malaria  of  the  complications. 
Anaemia  is  a  frequent  sequela,  but  is  rapidly  recovered  from  under  proper 
treatment.  Parotitis,  neuraligia,  pleurisy,  endocarditis,  and  severe  chronic 
enteritis  have  been  reported  as  sequelae  of  the  fever. 

Prognosis. — The  prognosis  is  always  grave,  the  mortality  varying  from 
10  to  30  per  cent.  The  mortality  varies  in  different  localities  and  in  different 
years,  being  sometimes  very  low  and  sometimes  appalling,  even  as  high  as  95 
per  cent.,  but  there  is  good  reason  to  believe  that  the  disease  has  often  been 
confused  with  yellow  fever,  and  that  thus  the  mortality  has  been  overestimated, 
especially  in  our  Southern  States.  Some  attacks  are  so  mild  as  hardly  to  be 
recognized,  but  in  the  majority  of  cases  the  prognosis  should  be  guarded. 
Unfavorable  prognostic  signs  are  decrease  in  the  quantity  of  urine,  excessive 
vomiting,  continued  hiccough,  and  somnolence.  Plehn  has  reported  cases 
in  which  sudden  death  has  occurred  from  thrombus  formation  in  the  large 
vessels  or  the  heart. 

Diagnosis. — Of  the  diseases  which  may  be  confused  with  haemoglobinuric 
fever  may  be  mentioned  yellow  fever,  paroxysmal  haemoglobinuria,  pernicious 
malaria  of  bilious  remittent  type,  and  Weil's  disease. 

Yellow  fever  may  easily  be  confused  with  haemoglobinuric  fever  by  one 
who  has  had  little  acquaintance  with  either  disease,  but  if  it  is  remembered 
that  in  yellow  fever  the  icterus  does  not  begin  until  the  third  or  fourth  day; 
that  haemoglobinuria  is  absent;  that  albuminuria  occurs  from  the  second  to  the 
fourth  day ;  and  that  the  temperature  is  characteristic,  it  is  not  difficult  to  make 
a  differential  diagnosis.  The  diagnosis  from  paroxysmal  haemoglobinuria  in  a 
region  where  both  diseases  occur  is  most  difficult,  and  may  be  impossible, 
but  in  the  majority  of  cases  the  greater  severity  of  the  symptoms  in  haemo- 
globinuric fever  will  serve  to  distinguish  it.  Pernicious  malarial  fever,  of  the 
bilious  remittent  type,  may  be  confused  with  haemoglobinuric  fever,  but  the 
presence  of  the  plasmodia  until  quinine  is  administered,  the  prompt  subsidence 
of  the  infection  under  quinine  treatment,  and  the  absence  of  haemoglobinuria, 
should  serve  to  enable  us  to  diagnose  the  malarial  nature  of  the  malady.  Weil's 
disease  might  be  mistaken  for  haemoglobinuric  fever,  but  haemoglobinuria  is 
not  present;  the  urine,  if  affected,  containing  multitudes  of  erythrocytes. 

I  have  mentioned  the  rare  occurrence  of  haemoglobinuria  following  the 
administration  of  quinine  in  malarial  patients.  This  condition  may  be  easily 
differentiated  from  haemoglobinuric  fever  by  the  absence  of  acute  symptoms, 
the  occurrence  of  the  condition  in  localities  known  to  be  free  from  "black  water" 
and  in  patients  who  have  never  been  exposed  to  the  latter  disease,  and  the  prompt 
disappearance  of  the  haemoglobinuria  upon  ceasing  the  administration  of 
quinine. 

Prophylaxis. — It  is  difficult  to  lay  down  rules  regarding  the  prophylaxis 


40-|  HAEMOGLOBINURIC    FEVER. 

of  a  disease  when  we  are  unacquainted  with  its  cause  and  the  method  of  its 
transmission,  but  we  have  good  reason  to  believe  that  the  measures  taken  for 
the  prophylaxis  of  malaria  are  also  quite  efficient  in  the  prophylaxis  of  this 
disease.  This  fact  has  been  used  as  an  argument  in  favor  of  the  malarial  origin 
of  black-water  fever,  but  it  is  simply  an  argument  in  favor  of  the  insect  trans- 
mission of  the  disease  and  of  its  protozoal  nature.  That  the  methods  adopted 
in  the  prophylaxis  of  malaria  are  also  efficient  in  the  prophylaxis  of  haemoglo- 
binuric  fever  is  merely  a  coincidence,  just  as  protection  from  the  mosquito  is 
efficient  in  the  prophylaxis  of  filariasis  and  dengue  as  well  as  in  malaria. 

A.  Plehn,  in  Cameroon,  has  found  that  the  prophylaxis  of  malaria  there 
has  not  only  resulted  in  a  reduction  in  the  number  of  malarial  infections,  but 
also  in  the  number  of  cases  of  haemoglobinuric  fever,  the  morbidity  of  malaria 
being  lowered  one-half,  while  that  of  black-water  fever  was  reduced  one-fourth, 
and  Moffatt  has  reported  similar  results.  It  is  therefore  recommended  that 
in  regions  infected  with  haemoglobinuric  fever  the  utmost  precautions  be 
taken  regarding  protection  from  the  bites  of  insects  and  that  prophylactic 
doses  of  quinine  be  administered. 

Treatment. — The  treatment  of  haemoglobinuric  fever  is  at  the  present 
time  most  unsatisfactory  because  of  the  divergent  opinions  held  by  observers 
regarding  the  use  of  quinine  in  this  disease.  It  would  be  unprofitable  here  to 
review  in  extenso  the  arguments  for  and  against  the  use  of  this  drug  in  haemo- 
globinuric fever,  for  the  question  is  still  far  from  settled,  and  statistics  are 
quoted  by  both  parties  favorable  to  their  contentions.  The  association  of 
haemoglobinuria  with  malaria  and  the  fact  that  haemoglobinuria  may  be 
produced  by  quinine  is  responsible  for  the  difference  in  opinion  regarding  the 
use  of  the  drug  in  treatment.  As  I  have  shown,  haemoglobinuric  fever  occurs 
without  coexisting  or  preexisting  malaria  and  in  patients  who  have  never 
taken  a  dose  of  quinine,  so  that  it  appears  that  the  question  is  simply  as  to 
whether  quinine  is  beneficial  in  haemoglobinuric  fever  or  whether  it  is  of  no 
value.  I  believe  that  there  is  little  evidence  that  indicates  that  quinine,  in 
uncomplicated  cases  of  haemoglobinuric  fever,  is  of  any  value,  and  it  may  well 
be  that  the  use  of  this  drug  in  large  doses  renders  the  blood  more  susceptible 
to  the  action  of  the  parasite  causing  haemoglobinuria.  When,  however,  the 
haemoglobinuric  fever  is  complicated  by  a  malarial  infection,  as  shown  by  the 
presence  of  the  plasmodia  in  the  blood,  quinine  should  be  given  in  doses  suf- 
ficient to  cure  the  malarial  complication,  but  it  should  not  be  given  unless  the 
plasmodia  can  be  found.  As  showing  the  very  slight  difference  between  the 
mortality  when  quinine  is  administered  and  when  it  is  not,  the  following  data, 
collected  by  Deaderick  are  of  interest.     Of  328  cases  treated  with  quinine, 

56  died,  a  mortality  of  17  per  cent.,  while  of  374  cases  treated  without  quinine, 

57  died,  a  mortality  of  15.2  per  cent.  Unfortunately,  we  are  ignorant  as  to 
how  many  of  these  cases  were  positive  for  the  malarial  plasmodia,  but  I  believe 
that  the  results  as  given  indicate  that  it  makes  but  little  difference  in  the 
mortality  of  haemoglobinuric  fever  whether  quinine  be  administered  or  not, 


HAEMOGLOBINURIC    FEVER.  405 

and  as  in  rare  instances  quinine  is  capable  of  producing  haemoglobinuria,  it 
is  better  to  abstain  from  the  use  of  the  drug  unless  the  malarial  plasmodia  are 
found  in  the  blood,  when,  of  course,  it  is  indicated  not  as  a  therapeutic  agent  in 
the  treatment  of  haemoglobinuric  fever,  but  as  a  specific  against  the  coincident 
malarial  infection. 

The  following  rules  governing  the  administration  of  quinine  in  haemo- 
globinuric fever  will  be  found  valuable  as  a  guide  to  the  use  of  the  drug  in 
this  disease: 

1 .  In  all  cases  showing  the  plasmodia  of  malaria  in  the  blood,  quinine  should 
be  administered  in  doses  sufficient  to  cure  the  existing  malarial  complication. 

2.  In  all  cases  which  do  not  show  the  presence  of  the  malarial  plasmodia 
during  the  first  day  of  the  attack,  quinine  should  be  withheld,  as  most  of  these 
cases  are  uncomplicated,  and  there  is  no  reason  to  believe  that  quinine  is  of 
any  value  in  the  treatment  of  uncomplicated  haemoglobinuric  fever. 

3.  In  cases  of  haemoglobinuria  arising  during  the  administration  of  quinine 
in  proven  malarial  infections,  the  administration  of  the  drug  should  be  discon- 
tinued for  a  day  or  two,  and  entirely  if  malarial  plasmodia  do  not  again  appear 
in  the  blood. 

4.  If  haemoglobinuric  fever  develop  during  an  attack  of  malaria  which 
is  already  being  treated  by  quinine,  but  in  which  the  plasmodia  can  still  be 
demonstrated  in  the  blood,  quinine  should  be  administered  until  the  plasmodia 
disappear. 

From  the  above  recommendations  it  is  evident  that  the  administration  of 
quinine  in  haemoglobinuric  fever  depends  entirely  upon  the  presence  of  the 
malarial  plasmodia,  and  the  drug  should  never  be  administered  in  this  disease 
unless  these  organisms  be  present.  Quinine  is  of  no  use  whatever  in  the  treat- 
ment of  haemoglobinuric  fever  per  se,  and  a  very  careful  examination  of  the 
blood  should  be  made  for  the  plasmodia  before  it  is  administered.  I  regard 
it  as  conclusively  proven  that  quinine  is  harmful  in  haemoglobinuric  fever 
unless  the  disease  is  complicated  by  malarial  infection,  and  this  would  ap- 
pear to  be  a  strong  proof  of  the  lack  of  relationship  between  the  two 
diseases. 

General  Treatment. — The  patient  suffering  from  haemoglobinuric  fever 
should  be  confined  to  bed  in  even  the  mildest  infections,  the  body  should  be 
kept  warm,  and  warm  drinks  will  be  found  most  useful  in  maintaining  the 
bodily  heat.  The  bowels  should  be  opened  by  a  dose  of  calomel  or  by  mag- 
nesium sulphate,  and  if  there  be  evidence  of  suppression  of  urine,  diuretics,  such 
as  potassium  citrate,  should  be  freely  administered,  hot  fomentations  applied 
over  the  region  of  the  kidneys,  and  an  exclusive  milk  diet  enforced.  If  vomit- 
ing be  slight,  liquid  nourishment  may  be  given  at  short  intervals,  but  in  cases  in 
which  the  vomiting  is  severe  nutrient  enemeta  should  be  given,  and  enemata  of 
salt  solution  should  be  administered  at  intervals  of  four  hours.  If  the  enemata 
are  not  retained,  the  salt  solution  should  be  injected  into  the  subcutaneous 
tissue  of  the  breast  or  of  the  loins.     The  use  of  morphine  in  this  disease  requires 


406  HAEMOGLOBINURIC    FEVER. 

great  caution  and  the  drug  should  never  be  administered  when  it  can  be 
avoided. 

The  use  of  stimulants  is  indicated  in  most  cases,  but  no  form  of  alcohol 
should  be  employed  in  the  treatment  of  haemoglobinuric  fever.  Strychnine, 
digitalis,  strophanthus  and  the  aromatic  spirits  of  ammonia  are  all  useful,  and 
the  inhalation  of  oxygen  is  warmly  advocated  by  Plehn. 

The  treatment  by  chloroform,  advised  by  Quennec,  has  proven  of  value  in 
some  instances,  but  as  it  was  combined  with  quinine  it  is  impossible  to  say  how 
efficacious  it  really  is  in  uncomplicated  cases  of  haemoglobinuric  fever.  He 
uses  the  following  mixture:  Chloroform,  6  gms.;  gum  arabic,  8  gms. ;  simple 
syrup,  250  gms.  The  entire  quantity  is  taken  every  24  hours,  a  sip  being  taken 
every  10  or  15  minutes.  He  claims  for  the  treatment  that  it  controls  vomiting, 
diminishes  albuminuria,  and  increases  the  quantity  of  the  urine.  The  Stern- 
berg treatment  of  yellow  fever,  by  a  mixture  of  bichloride  of  mercury  and 
sodium  bicarbonate,  has  been  used  by  some  practitioners  with  good  results. 
The  method  of  Vincent,  who  uses  calcium  chloride,  a  well-known  antihemolysin, 
is  deserving  of  consideration  in  the  treatment  of  this  disease,  as  it  is  founded 
upon  sound  scientific  principles.  The  drug  is  given  in  doses  of  from  4  to  6 
grammes  per  day  by  the  mouth,  or  from  1  to  2  grammes  hypodermically, 
during  the  acute  symptoms,  and  in  every  case  in  which  it  has  been  administered 
the  results  have  been  such  as  to  indicate  that  it  is  more  nearly  a  specific  than 
any  remedy  so  far  used  in  the  treatment  of  this  disease. 

The  fever  seldom  requires  treatment,  as  the  temperature  is  not  excessive 
and  does  not  last  many  days,  but  in  cases  in  which  there  is  hyperpyrexia  spong- 
ing with  tepid  water  and  alcohol  is  generally  sufficient;  vomiting,  often  most 
distressing,  may  be  benefited  by  mustard  plasters  over  the  epigastrium,  the 
sucking  of  cracked  ice,  the  drinking  of  carbonated  beverages,  and,  as  a  last 
resource,  the  hypodermic  injection  of  morphine.  Champagne  is  permissible 
in  cases  in  which  the  vomiting  is  severe,  the  strength  exhausted,  and  no  food  can 
be  retained  by  the  stomach.  It  should  be  given  in  small  quantities,  frequently 
repeated.  During  convalescence  the  diet  should  be  light  but  nutritious,  the 
patient  should  be  warned  against  overexertion  and  the  use  of  alcoholics,  and 
every  measure  should  be  taken  to  avoid  mental  worry  and  nervous  excitement. 
If  possible,  the  patient  should  leave  the  infected  locality  and  never  return  to  it, 
for  longer  residence  will  very  often  result  in  recurrences  of  the  haemoglobinuric 
attack. 

From  what  has  been  said  of  the  treatment  of  haemoglobinuric  fever  it  is 
evident  that  as  yet  we  have  discovered  no  specific  for  the  disease,  and  that 
the  treatment  is  wholly  empirical,  due  to  our  ignorance  of  the  exact  etiological 
factor.  If,  as  is  held  by  many,  haemoglobinuric  fever  is  due  to  the  malarial 
Plasmodia,  why  is  it  that  treatment  with  quinine  is  not  successful,  and  if,  as 
others  hold,  it  is  due  to  quinine,  how  is  it  that  the  continuation  of  the  use  of  this 
drug  in  treatment  does  not  lead  to  a  fatal  result  in  the  majority  of  cases?  The 
truth  is  that  quinine  is  beneficial  in  haemoglobinuric  fever  just   so  long  as 


HAEMOGLOBINURIC    FEVER.  407 

malarial  plasmodia  are  found  in  the  blood,  thus  proving  that  the  malaria 
infection  is  merely  a  coincidence,  for  the  drug  is  absolutely  useless  in  those 
cases  of  haemoglobinuric  fever  in  which  no  malarial  plasmodia  can  be  demon- 
strated. The  only  conclusion  possible  to  an  unprejudiced  student  after  care- 
fully considering  the  epidemiology,  symptomatology,  and  therapeutics  of 
haemoglobinuric  fever  is  that  neither  malaria  nor  quinine  have  anything  to  do 
with  its  etiology,  but  that  it  is  caused  by  some  parasite,  hitherto  undiscovered, 
in  all  probability  belonging  to  the  Protozoa. 

Literature  upon  Haemoglobinuric  Fever. 

1861.      Dutrouleau.      Traite  des  maladies  des  Europeans  dans  les  pays  chauds. 

Paris. 
1874.      Berenger-Feraud.      De  la  fievre  bilieuse  melanurique  des  pays  chauds. 

Paris. 

1878.  Idem.      De  la  fievre  bilieuse  inflammatoire  aus  Antilles  et  dans  l'Amerique 
tropicale,  etc.      Paris. 

1879.  Idem.  Note  sur  deux  cas  de  fievre  melanurique.  Archiv.  de  Med.  navale. 
1887.      Loeff,  Van  Der.      Monatsblatter  f.  praktische  Dermatologie. 

1889.      Rossoni.      Studi  clinici  sulle  emoglobinurie.      Milan. 

1892.  Baccelli.      Ueber  einen  Fall  von  nicht  paroxysmaler  Hamoglobinurie. 
Verhandlungen  des  Congresses  fur  innere  Medicin  zu  Wiesbaden. 

1893.  Davidson.      Hygiene  and  Dieases  of  Warm  Climates.     London. 

1893.  Bastianelli    and    Bignami.      Sulle    emoglobinurie    da    malaria.     Bull, 
della  Soc.  Lancisiana. 

1894.  Studel.      Die  perniciose  Malaria  in  Deutsch  Ostafrika.      Leipsic. 

1894.  Pfeiffer,  L.      Die  Protozoen  als  Krankheitserreger.     Jena. 

1895.  Murri.      Sull'  intossicazione  da  chinino.      II  Policlinico. 

1895.  Kuchel.      Ueber  Schwarzwasserfieber,  etc.      Deutsch.  med.  Wochenschr., 
1895. 

1896.  Bastianelli.      Le   emoglobinurie    da   malaria   secondo   i   recenti   studi. 
Annali  di  Medicina  navale,  1896. 

1896      Berthier,  A.    Pathogenie  et  traitement  de  l'haemoglobinurie  paludeenne. 
Archiv.  de  medecine  experimentale,  1896. 

1896.  Manson.      British  Medical  Journal,  vol.  i,  p.  257.      Also  Trans.  Epidemi- 
ological Society,  vol.  xii,  1892-93. 

1897.  Tomaselli.      La  intossicazione  chinica  el  infezione  malarica.      Catania. 

1898.  Plehn,  F.      Die  Kamerun  Kiiste.      Berlin. 

1899.  Crosse.      Black-water  Fever.     London. 

1900.  Marchiafava  and  Bignami.      Malaria,  in  Twentienth  Century  Practice, 
No.  19,  New  York. 

1900.  Marchoux.      Rapport  au  congres  de  Paris,  1900. 

1 90 1.  Daniels.      Reports   to   the   Malaria   Committee   of  the   Royal   Society, 
5th  Series. 

1 90 1.  Thayer.      Lectures  upon  the  Malarial  Fevers.      New  York. 

1902.  Celli.      Archives  Italian  Soc.  de  Biologie,  p.  211. 

1903.  Plehn,  A.  Archiv.  f.  Schiffs-  und  Tropenhyg.,  Bd.  vii,  p.  541  and  p.  270. 
1903.  Stephens.      Thompson- Yates  Laboratory  Reports,  vol.  v,  Part  i,  p.  217. 

1906.  Cassigrandi.      Atti  della  Soc.  per  gli  Studi  della  Malaria,  p.  115. 

1907.  Stephens,  J.   W.  W.      Black-water  Fever.      System  of  Medicine,  Allbutt 
and  Rolleston,  vol.  ii,  Part  ii,  p.  289,  London. 


408  HAEMOGLOBINURIC    FEVER. 

1907.      Idem.      Black-water  Fever.      Osier's  "Modern  Medicine,"  vol.  i,  p.  449. 
1007       Daniels.      Laboratory  Studies  in  Tropical  Medicine.      Second  Edition, 
London  and  Philadelphia. 

1907.  Manson.     Tropical  Diseases.      Fourth  Edition.     London  and  New  York. 

1908.  Stephens  and  Christophers.  The  Practical  Study  of  Malaria  and 
other  Blood  Parasites.      London. 

1 90S.  Plehn,  A.  The  Cause,  Prevention,  and  Treatment  of  Haemoglobinuric 
Fever  in  Warm  Countries.  Jour,  of  Tropical  Med.  and  Hyg.,  vol.  xi, 
Xo.  19,  p.  294. 

1 90S.      Deaderick,  W.  H.      Haemoglobinuric  Fevers.      Memphis  Med.  Monthly, 
Dec,  1907,  and  March,  1908. 
See  also  the  treatises  upon  "Malaria"  by  Kelsch  and  Kiener,  Laveran,  Man- 

naberg,  and  Celli. 


PART  VII. 

THE  BLOOD  PROTOZOA  OF  MAN. 


Plate  IV 


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2  3 

10 


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C.     F.    CRAIG,    DEL. 


EXPLANATION  OF  PLATE  IV. 

Leishmania    donovani.      Leishman-Donovan     Bodies.      Stained    with     Wright's 
Stain. 

i  to  10.   Various  forms   of  Leishmania  donovani,  the  protoplasm   stained 
blue,  the  chromatin,  red. 

10.  Matrix  containing  several  Leishmania  donovani. 

1 1 .  Large  endothelial  cell  containing  many  Leishmania  donovani. 

12  to  34.   Various  cultural   forms  of   Leishmania  donovani.      Many  of  these 
forms  show  division  into  two  parasites. 

34.   A  so-called  "rosette"  formed  by  cultural  forms  of  Leishmania  donovani. 
Fig.  A.      Trypanosoma  gambiense,  stained  with  Wright's  stain. 
Fig.  B.      Spirochceta  duttoni,  stained  with  Wright's  stain. 

1.  Spirochasta  showing  peculiar  out-growths  along  its  course,   containing 
chromatin. 

2.  Spirochasta  undergoing  longitudinal  division. 

3.  Spirochasta  undergoing  transverse  division. 

Fig.  C.      Various  forms  of  Histoplasma  capsulatum.      (After  Darling.) 

In  all  of  these  figures  the  red  equals  chromatin  and  the  blue,  protoplasm. 


CHAPTER  I. 
The   Leishman-Donovan   Bodies.      Leishmania-donovani. 

Since  their  discovery,  the  Leishman-Donovan  bodies,  or  Leishmania-dono 
vani,  have  proven  of  the  greatest  interest  to  students  of  protozoology  and 
tropical  medicine,  and  have  been  accepted  as  the  cause  of  a  form  of  tropical 
splenomegaly,  commonly  known  as  kala-azar  or  "dum-dum  fever."  Wright's 
discovery  of  a  similar  organism  in  tropical  ulcer  (Delhi  boil)  and  the  discovery 
of  Pianese  and  Nicolle  in  infantile  splenic  anaemia  of  a  parasite  indistinguish- 
able morphologically  from  these  organisms  has  awakened  renewed  interest  in 
the  subject,  and  would  appear  to  indicate  that  parasites  belonging  to  the  genus 
Leishmania  are  more  widely  distributed  than  we  had  supposed  and  that  they 
constitute  a  most  important  factor  in  the  etiology  of  disease. 

While  it  is  far  more  common  to  find  Leishmania-donovani  in  the  liver  and 
spleen  than  in  the  blood,  it  is  true  that  they  may  be  demonstrated  in  the  per- 
ipheral blood,  and,  therefore,  have  to  be  considered  in  any  discussion  of  the 
protozoa  of  the  blood. 

Historical. — The  form  of  tropical  splenomegaly  known  as  kala-azar  has 
long  been  studied  in  India,  where  it  was  first  described,  and  is  a  unique  illustra- 
tion of  the  fallibility  of  medical  opinion  and  deduction.  Clarke  first  called  the 
attention  of  medical  men  to  kala-azar  in  1882,  when  he  studied  it  in  Assam,  and 
states  that  the  disease  was  recognized  in  1869.  For  many  years  it  was  regarded 
as  a  persistent  form  of  malaria,  or  malarial  cachexia,  and  it  was  not  until  the 
discovery  of  the  Leishmania-donovani  that  the  theory  of  the  malarial  nature  of 
this  malady  was  abandoned,  although  many  other  theories  had  developed 
regarding  its  etiology.  Thus,  Giles,  after  careful  study,  announced  in  1889 
that  malaria  had  nothing  to  do  with  the  etiology  of  kala-azar,  but  that  the 
disease  was  due  to  Anchylostoma  duodenale,  as  most  of  the  patients  suffering 
from  the  disease  showed  ova  of  this  worm  in  their  faeces.  Bentley,  in  1903, 
regarded  kala-azar  as  a  severe  form  of  Malta  fever;  while  in  1896,  Leonard 
Rogers,  and  in  1898,  Ronald  Ross,  considered  the  disease  as  malarial  in  nature, 
Rogers  claiming  that  it  was  a  fatal  form  of  malarial  fever,  while  Ross  con- 
sidered it  as  malarial  fever  complicated  by  some  secondary  infection.  Manson 
was  one  of  the  first  to  suggest  that  kala-azar  was  a  disease  entity,  due  to  some 
undiscovered  parasite,  probably  a  trypanosoma,  and  it  is  interesting  to  observe 
how  closely  this  careful  investigator  guessed  at  the  truth. 

To  Leishman  belongs  the  credit  of  first  observing  and  describing,  in  a 
soldier  of  the  English  Army,  the  true  parasite  of  kala-azar.  In  1900  he  had 
observed  in  the  splenic  pulp  obtained  at  autopsy  from  a  soldier  who  had  died  of 

411 


41^  THE    BLOOD    PROTOZOA    OF    MAX. 

kala-azar  small  round  or  oval  bodies,  possessing  a  large  and  small  chromatin 
mass;  at  that  time  he  did  not  call  attention  to  them,  but  later,  having  found 
similar  bodies  in  the  blood  of  a  rat  infected  with  the  parasite  of  nagana,  he 
published  a  paper  (in  1903)  calling  attention  to  the  matter,  and  suggesting  that 
the  bodies  observed  by  him  in  the  splenic  pulp  of  the  soldier  might  be  degenera- 
tive forms  of  a  trypanosoma.  In  the  same  year  Donovan  found  the  same 
parasite  in  splenic  smears  Obtained  at  autopsy  and  in  blood  from  the  spleen 
obtained  during  life,  and  their  presence  was  quickly  confirmed  by  Marchand 
and  Manson  in  patients  suffering  from  kala-azar.  The  results  obtained  by  the 
investigators  mentioned  awakened  great  interest  in  the  subject  and  during  the 
next  few  years  the  fact  was  definitely  demonstrated  that  patients  suffering  from 
this  disease  invariably  present  within  their  viscera,  and  often  in  the  peripheral 
blood,  the  parasite  described  by  Leishman  and  Donovan,  and  at  the  present 
time  this  parasite  is  accepted  as  the  cause  of  the  disease.  That  it  is  the  cause 
has  not  been  absolutely  proven,  but  the  fact  that  it  is  found  always  and  only  in 
patients  afflicted  with  this  fever  is,  I  believe,  sufficient  to  prove  that  it  stands  in 
etiological  relationship  to  kala-azar. 

Geographical  Distribution. — For  years  it  was  thought  that  kala-azar 
was  a  disease  peculiar  to  India,  but  after  the  discovery  of  the  parasite  it  was 
found  that  the  disease  was  widely  distributed  throughout  the  Orient  and  every 
year  the  geographical  distribution  of  this  organism  is  added  to  by  investigators. 
At  first  localized  in  certain  regions  in  India,  it  has  gradually  spread  until  at  the 
present  time  it  is  a  veritable  scourge  in  various  regions  of  that  country  and  is 
said  to  be  still  spreading. 

It  is  common  in  Ceylon  and  Burma,  and  has  been  found  in  China,  in 
Arabia,  Egypt,  the  Soudan,  Algeria,  Tunis,  and  in  other  parts  of  Africa. 
Although  it  has  been  carefully  searched  for  in  the  Philippine  Islands,  it  has  not 
as  yet  been  demonstrated  there.  The  occurrence,  however,  of  a  form  of 
tropical  splenomegaly  in  these  islands  is  suggestive,  and  further  research  may 
show  that  Leishmania-donovani  is  the  etiological  factor  in  some  of  these  cases. 
While  serving  on  the  U.  S.  Army  Board  for  the  Study  of  Tropical  Diseases  in 
the  Philippine  Islands,  Ashburn  and  I  repeatedly  examined  the  splenic  pulp 
from  a  native  suffering  from  splenomegaly  accompanied  by  attacks  of  fever,  but 
were  not  able  to  find  the  Leishman-Donovan  bodies,  although  hours  were 
spent  in  the  search  and  many  splenic  punctures  were  performed.  While  in 
this  case  the  condition  was  obviously  not  due  to  Leishmania-donovani,  it  is 
possible  that  it  may  be  the  etiological  factor  in  some  of  the  cases  of  enlarged 
spleen  not  infrequently  observed,  and  the  subject  should  be  given  careful 
study. 

Biological  Position. — The  biological  position  of  the  Leishman-Donovan 
parasite  has  occasioned  much  controversy,  and  it  is  impossible  to  classify  this 
organism  permanently  until  we  know  every  point  regarding  its  morphology  and 
life  history.  At  the  present  time  a  provisional  classification  has  been  agreed 
upon,  in  which  the  Leishman-Donovan  body  is  placed  in  the  genus  Leishmania 


THE    BLOOD    PROTOZOA    OF    MAN.  413 

and  species  donovani,  the  proper  name  for  the  organism  being  Leishmania- 
donovani. 

Leishman  considered  the  organisms  as  degenerated  forms  of  a  trypanosoma, 
but  later  investigations  have  shown  that  trypanosoma  forms  are  never  found  in 
the  human  body,  and  while  the  development  of  flagellated  forms  in  cultures 
might  appear  to  confirm  Leishman's  theory,  the  flagellated  forms  are  distinct 
morphologically  from  any  known  trypanosoma.  Laveran,  Mesnil,  and  Donovan 
regard  the  parasite  as  a  Piroplasma,  as  they  have  seen  forms  which  they  have 
interpreted  to  be  intracellular  in  the  red  blood-corpuscle,  and  Laveran  named  it 
" '  Piroplasma-donovani.,}  The  existence  of  forms  occurring  within  the  red  blood- 
corpuscles  is  very  doubtful  and  the  further  fact  that  the  organism  possesses  two 
clumps  of  chromatin  and  that,  in  cultures,  flagellate  forms  develop,  definitely 
place  it  in  some  other  genus.  Rodgers  places  it  in  the  genus  Herpetomonas  and 
Birt  thinks  that  it  may  be  the  gregariniform  stage  of  a  Herpetomonas  because  of 
its  resemblance  to  the  small  ovoid  forms  of  Crithidia  fasciculata.  Ross,  who 
considers  it  a  distinct  form  of  protozoa,  suggested  placing  it  in  a  new  genus, 
Leishmania,  and  named  it  Leishmania-donovani,  and  until  we  know  more  of  its 
life  history  it  is  considered  wise  by  most  protozoologists  to  adopt  the  classifica- 
tion suggested  by  Ross. 

The  discovery  by  Wright,  of  Boston,  of  a  similar  parasite  in  tropical 
ulcer,  and  by  Pianese  and  Nicolle  in  infantile  splenic  anaemia,  has  added 
two  more  members  to  the  genus  Leishmania;  the  organism  associated  with 
tropical  ulcer  being  called  Leishmania  tropica,  while  that  associated  with 
infantile  splenic  anaemia  is  known  as  Leishmania  infantum. 

The  Morphology  of  Leishmania-donovani. — The  morphology  of 
Leishmania-donovani  in  the  human  body  and  in  cultures  varies  so  widely  that  it 
is  necessary  to  consider  each  separately.  The  flagellate  forms  observed  in 
cultures  have  never  been  observed  in  the  peripheral  blood  or  in  smears  from 
any  of  the  organs  of  the  body,  so  that  it  is  evident  that  the  flagellate  stage  of 
growth  is  extracorporeal,  and  probably  occurs  within  some  insect,  as  will  be 
shown  later  in  considering  the  very  interesting  work  of  Patton. 

Morphology  in  Man. — The  parasite  consists  essentially  of  a  small  mass 
of  protoplasm  surrounded  by  a  limiting  membrane,  and  enclosing  two  chromatin 
clumps,  one  considerably  larger  than  the  other.  The  organisms  vary  some- 
what in  size,  measuring  from  2  to  4  microns  in  length  by  1.5  to  2  microns  in 
breadth. 

In  shape  the  Leishman-Donovan  bodies  are  generally  oval,  but  may  be 
elongated  slightly  or  perfectly  spherical.  Pyriform  organisms  are  observed 
and  led  to  the  classification  of  the  organism  as  a  pyroplasma,  but  it  is  probable 
that  most,  if  not  all,  of  the  organisms  presenting  a  pyriform  shape  are  so 
distorted  in  the  process  of  making  the  smear.  In  the  fresh  preparations 
the  organism  is  never  observed  to  change  its  shape,  thus  indicating  that  it 
does  not  possess  amoeboid  motility. 

The  limiting  membrane  is  well  defined  in  the  fresh  specimen,  but  in  stained 


414  THE    BLOOD    PROTOZOA    OF    MAN. 

preparations  it  is  commonly  dim  or  may  appear  absent,  although  in  deeply 
stained  specimens  it  may  be  very  well  defined  as  a  bluish,  clearly  cut  membrane 
surrounding  the  almost  unstained  and  vacuolated  protoplasm.  It  does  not 
contain  any  trace  of  chromatin. 

The  protoplasm,  in  fresh  specimens,  appears  homogeneous  and  refractive. 
It  does  not  stain  well  and  appears  vacuolated  in  stained  specimens,  the  chroma- 
tin masses  appearing  to  lie  in  a  large  vacuole  surrounded  by  the  limiting 
membrane.  The' protoplasm,  when  stained  by  any  of  the  modifications  of  the 
Romanowsky  stain,  appears  faintly  bluish  in  color  in  well-stained  specimens, 
the  color  being  most  marked  around  the  periphery  of  the  organism  just  within 
the  limiting  membrane. 

The  two  chromatin  masses  lie  within  the  cytoplasm,  one,  the  larger,  being 
situated  at  the  center  or  near  the  periphery,  while  the  smaller  mass  is  situated 
opposite  the  larger,  near  the  periphery  of  the  parasite.  In  rare  instances 
these  two  masses  of  chromatin  are  joined  together  by  a  bluish-stained  portion 
of  cytoplasm.  The  larger  chromatin  mass,  or  nucleus,  is  generally  oval  in 
shape,  although  not  infrequently  it  is  perfectly  spherical,  and  stains  a  dull 
red  or  pink,  much  less  intense  in  color  than  the  staining  of  the  smaller  mass. 
Manson  and  others  believe  that  the  nucleus,  prior  to  division,  moves  toward  the 
periphery,  and  becomes  elongated,  and  it  is  certain  that  when  the  nucleus  is 
situated  at  the  center  of  the  parasite  it  is  always  oval  or  spherical  in  shape, 
and  that  the  elongated  forms  are  only  observed  at  the  periphery.  The  smaller 
chromatin  mass  (centrosome  or  blepharoplast)  is  generally  rod-shaped,  and 
stains  a  very  intense  scarlet  with  the  Romanowsky  stains,  sometimes  appearing 
almost  black.  It  is  situated  opposite  the  nucleus,  and  the  rod  may  point 
toward  the  latter  or  lie  at  any  angle  to  it;  this  body  exhibits  no  distinct 
structure,  staining  evenly  throughout  and  appearing  like  a  bacillus.  Chris- 
tophers and  James  have  observed  a  tail-like  prolongation  of  the  chromatic 
substance  of  the  blepharoplast,  extending  from  it  at  right  angles  to  its  long  axis, 
the  significance  of  which  has  not  yet  been  determined. 

In  smears  from  the  liver  and  spleen  the  parasites  may  occur  free,  lying 
singly  or  in  groups,  or  they  are  observed  within  the  endothelial  cells  in  large 
numbers,  or  lying  in  masses  in  a  granular  faintly  stained  matrix,  the  re- 
mains of  the  degenerated  cell.  In  man  Leishmania-donovani  are  intracellular 
organisms,  invading  the  endothelial  cells  of  the  organs  and  only  appearing  free 
in  the  blood  plasma  or  the  juices  of  the  organs  after  they  have  been  liberated 
by  the  destruction  of  the  host  cell.  The  parasite  invades  the  protoplasm  of  the 
host  cell  and  apparently  multiplies  within  it,  causing  great  enlargement  and 
ultimate  destruction  of  the  nucleus  and  degeneration  of  the  entire  cell.  In  the 
peripheral  blood  and  in  smears  of  the  various  organs,  multitudes  of  these 
parasites  may  be  observed  within  phagocytes,  which  undoubtedly  play  a  very 
important  part  in  their  destruction  within  man.  In  the  irregular  masses  of 
granular  substance  already  mentioned  the  parasites  may  occur  in  very  large 
numbers,  and  I  have  counted  in  one  such  matrix  over  three  hundred  parasites. 


THE    BLOOD    PROTOZOA    OF    MAN.  415 

It  is  not  uncommon  to  observe  atypical  parasites  in  these  granular  masses, 
in  which  either  the  nucleus  or  blepharoplast  is  missing  and  the  limiting 
membrane  remains  unstained. 

Manson  and  Low,  who  have  contributed  valuable  studies  upon  the  morph- 
ology of  the  Leishman-Donovan  body,  distinguish  several  types  of  the  organism 
in  stained  films,  and  as  their  description  applies  to  what  is  usually  observed  in 
smears  made  from  the  liver  or  spleen,  I  give  it  in  their  own  words: 

"In  the  stained  films  we  recognize  the  following: 

"1.  Oat-shaped,  oval,  and  circular  bodies,  clearly  defined  in  outline, 
stained  a  faint  blue,  and  having  a  rather  large  and  deeply  stained,  usually 
spherical  nucleus,  lying  against  the  capsule  about  the  middle  of  the  parasite, 
and  a  still  more  deeply  stained,  short,  bacillus-like  body  on  the  opposite  side 
of  the  capsule,  but  directed,  as  a  rule,  but  not  invariably,  toward  the  nucleus 
at  various  angles.  In  a  few  instances  this  bacillus-like  centrosome,  if  so  we 
may  call  it,  is  represented  by  a  point." 

2.  "Similar  and  generally  rather  larger  bodies  with  the  nucleus  larger  and 
less  deeply  stained  or  with  the  nucleus  spread  out  as  a  deeply  stained  layer 
on  the  inside  of  the  capsule,  and  in  the  usual  position,  that  is,  vis-a-vis  to  the 
centrosome.  In  the  latter  type  of  parasite,  with  the  exception  of  the  nucleus 
and  centrosome,  the  contents  of  the  capsule  are  very  faintly  stained." 

3.  "The  foregoing  bodies  in  association  with  a  faintly  staining  and  slightly 
granular  substance,  which  may  be  either  regularly  disposed  around  them  or 
attached  to  one  side  of  them  as  a  roundish  or  flocculent  irregular  mass." 

4.  "Two  of  the  oval  bodies  closely  applied  to  each  other,  one  of  the  bodies 
being  smaller  than  the  other.  Occasionally  in  these  twin  bodies  their  respective 
nuclei  and  centrosomes  are  disposed  symmetrically." 

The  last  named  form  of  parasite  is  a  dividing  form  or  one  in  which  division 
is  complete.  The  arrangement  of  the  centrosome  as  a  single  small  dot  of 
chromatin  is  not  uncommon  in  the  large  collections  of  parasites  within  a 
granular  matrix,  and  very  often,  in  such  instances,  it  is  impossible  to  distinguish 
all  of  the  morphological  features  which  have  been  described  as  characteristic 
of  the  Leishman-Donovan  body. 

The  morphology  of  the  forms  undergoing  division  will  be  considered  in 
speaking  of  the  methods  of  multiplication  of  these  parasites.     (See  Plate  IV.) 

Morphology  in  Cultures. — In  1904,  Leonard  Rogers,  of  the  Indian 
Medical  Service,  first  succeeded  in  cultivating  the  Leishman-Donovan  bodies, 
and  proved  that  in  such  cultures  true  flagellated  bodies  developed  which, 
on  account  of  their  resemblance  to  the  trypanosomatidae,  were  described  by 
him  as  trypanosomes,  and  so  regarded  until  further  culture  experiments 
definitely  proved  that  they  were  not  morphologically  identical  with  any  known 
form  of  trypanosoma. 

The  first  morphological  change  observed  in  the  parasite  in  cultures  is  a 
considerable  enlargement  of  the  nucleus  (macronucleus),  the  chromatin  at  the 
same  time  becoming  less  compact  and  staining  less  intensely;  coincidently  with 


416  THE   BLOOD   PROTOZOA   OF    MAN. 

the  enlargement  of  the  nucleus  the  protoplasm  apparently  increases  in  amount 
and  the  entire  organism  becomes  larger;  the  centrosome  (micronucleus)  does 
not  enlarge,  and  remains  unchanged  throughout  the  entire  process  of  flagella- 
tion. After  the  changes  described  the  organism  undergoes  division  by  simple 
fission  at  least  twice,  the  resulting  bodies  being  round  or  oval  in  shape  and  pos- 
sessing the  same  morphology  as  when  observed  in  man. 

After  this  preliminary  division  has  been  completed  there  appears  in  the 
protoplasm  a  vacuole  which  contains  an  eosin  staining  substance,  called  by 
Rogers  the  "eosin-spot,"  which  is  always  situated  near  the  blepharoplast 
(micronucleus).  The  parasite  now  becomes  elongated  and  ovoid  in  shape,  one 
end  being  more  narrow  than  the  other,  and  the  blephoroplast  and  eosin  con- 
taining vacuole  become  situated  at  one  end  of  the  body  of  the  organism,  gen- 
erally the  more  pointed  extremity.  After  attaining  this  position  the  eosin 
vacuole  enlarges  and  finally  reaches  the  surface  of  the  body,  where  it  appears  to 
liberate  a  fringe-like  structure  which  eventually  becomes  a  flagellum.  This, 
when  fully  developed,  is  seen  to  arise  from  the  blepharoplast  (micronucleus) 
as  in  the  trypanosomes.  No  undulating  membrane  ever  develops,  nor  is  there 
any  approximation  of  the  blepharoplast  and  nucleus  at  any  stage  in  the  process 
of  flagellar  formation.  After  the  liberation  and  development  of  the  flagellum 
the  entire  organism  elongates,  the  extremity  furthest  away  from  the  blepharo- 
plast becoming  narrow  and  pointed,  while  that  from  which  the  flagellum  arises 
is  more  rounded  in  appearance;  the  nucleus  is  situated  toward  the  non-flagel- 
lated extremity  in  some  instances  but  is  central  in  the  majority  of  the  parasites. 

The  flagellated  forms,  the  development  of  which  has  just  been  described, 
divide  into  spirillar-like  forms,  division  being  preceded  by  the  appearance  of 
chromatin  granules,  which  are  arranged  in  pairs  throughout  the  protoplasm. 
The  division  of  the  flagellate  forms  occurs  longitudinally  and,  according  to 
Leishman,  more  than  two  spirillar-like  organisms  result  from  such  division, 
but  Rogers  describes  an  equal  division  of  the  organism  into  two  spirillar-like 
forms.  According  to  Rogers,  the  blepharoplast  (micronucleus)  and  flagellum 
first  divide,  followed  by  the  division  of  the  nucleus,  and  the  longitudinal  split- 
ting of  the  body  into  two  equal  portions,  each  of  which  repeats  the  process  of 
division  within  a  short  time.  This  rapid  division  results  in  the  formation  of 
rosettes  in  which  the  flagella  point  toward  the  center  of  the  rosette.  It  will  be 
observed  that,  according  to  Roger's  description,  the  flagellum  of  each  organism 
is  already  formed  when  division  is  complete,  while,  according  to  Leishman, 
the  flagellum  is  developed  after  division,  which  has  resulted  in  the  formation  of 
several  individuals.  Minchin  also  states  that  the  process  of  division  would 
appear  to  be  "a  process  of  markedly  unequal  longitudinal  fission."  As<  a 
matter  of  fact,  both  forms  of  division  occur,  equal  longitudinal  division  being 
most  commonly  observed;  but  not  infrequently  an  organism  may  be  observed 
in  which  the  splitting  off  of  the  minute  spirillar-like  forms  described  by 
Leishman  is  occurring.  The  latter  forms  are  at  first  devoid  of  a  flagellum, 
but  one  is  developed  rapidly  and  the  organism  becomes  very  actively  motile. 


THE    BLOOD    PROTOZOA    OF    MAN. 


417 


The  forms  resulting  from  equal  longitudinal  division  are  at  first  pear-shaped 
and  broad,  but  soon  elongate  and  become  actively  motile,  much  more  so  than 
were  the  parent  bodies  at  the  time  of  division;  the  blepharoplast,  from  which 
arises  the  flagellum,  is  situated  anteriorly,  while  the  nucleus  is  at  or  near  the 
center  of  the  body.  After  the  formation  of  the  flagellated  forms  no  further 
development  occurs  in  cultures,  and  the  organisms  soon  perish.  The 
flagellated  forms  of  the  Leishman-Donovan  body  appear  in  cultures  between 
the  third  and  sixth  day  after  inoculating  the  culture  media. 


hit  utu-uJ 

M 

Fig.  26. — Leishmania  donovani.     (After  Leishman.) 
1-3,  Kala-azar  parasites  as  observed  in  man.     At  3  is  seen  a  large  mononuclear  cell  contain- 
ing four  parasites;  4-14,  Leishmania  donovani  as  observed  in  cultures  (cultural  forms).     At 
12  and  13  are  seen  parasites  dividing  into  the  spirochaete  forms  described  by  Leishman. 

Multiplication. — In  man,  Leishmania-donovani  multiplies  in  two  ways:  by 
simple  fission,  binary  in  character,  and  by  multiple  fission.  In  the  former  the 
nucleus  first  divides  into  two,  quickly  followed  by  the  division  of  the  blepharo- 
plast (micronucleus)  into  two  portions,  after  which  the  body  of  the  parasite 
divides  longitudinally  into  two  equal  portions,  each  of  which  contains  a  nucleus 
27 


418  THE    BLOOD    PROTOZOA    OF    MAN. 

and  a  blepharoplast.  When  multiple  fission  occurs,  the  parasite  becomes 
nearly  twice  as  large  as  normal,  the  nucleus  and  blepharoplast  divide  into 
three,  four  or  more  equal  portions,  and  the  protoplasm  shows  lines  of  cleavage 
surrounding  each  pair  of  chromatin  masses,  the  nucleus  and  blepharoplast. 
In  this  way  the  multiplying  organism  resembles  somewhat  a  malarial  rosette, 
but  may  be  easily  distinguished  by  observing  that  each  segment  consists  of  a 
mass  of  protoplasm,  and  two  chromatin  masses,  one  larger  than  the  other,  and 
placed  opposite  one  another,  the  smaller  being  rod-shaped.  The  organisms 
resulting  from  this  mode  of  multiplication  are  much  smaller  than  the  parent 
organism  and  are  sometimes  so  minute  as  to  require  very  careful  examination  in 
order  to  demonstrate  them. 

The  multiplication  of  the  parasites  in  cultures  has  already  been  described, 
and,  as  will  be  shown,  Patton  has  demonstrated  a  similar  method  of  multiplica- 
tion in  the  stomach  of  a  certain  species  of  bed-bug. 

Cultivation. — -Until  1904  nothing  was  known  regarding  the  extracorporeal 
existence  of  the  Leishman-Donovan  body,  but  in  that  year  Rodgers  was  suc- 
cessful in  demonstrating  that  this  organism  can  be  cultivated  outside  of  man 
and  that  its  developmental  cycle  comprised  not  only  the  forms  observed  in  the 
infected  patient,  but  that  it  also  possessed  a  flagellate  stage  which  only  developed 
when  the  organism  was  removed  from  the  blood  or  organs  of  its  host.  The 
further  researches  of  Patton,  which  would  appear  to  prove  that  the  same  forms 
occur  in  the  stomach  of  the  bed-bug,  indicate  that  this  insect  is  the  transmitting 
agent  of  the  disease,  and  that  the  flagellate  forms,  as  in  malaria,  only  develop 
within  an  intermediate  host.  Rogers'  cultivation  experiments  were  promptly 
repeated  and  confirmed  by  other  investigators,  notably  Christophers,  Leishman, 
Chatterjee,  Statham  and  Patton.  I  have  already  described  the  development 
of  the  Leishman-Dononan  bodies  in  cultures  and  will  here  discuss  briefly  the 
method  most  successful  in  cultivation. 

Rogers  first  endeavored  to  grow  the  parasites  by  adding  to  blood  ob- 
tained by  splenic  puncture  from  kala-azar  patients,  about  1  c.c.  of  sterile  salt 
solution  containing  5  to  10  per  cent,  of  sodium  citrate,  and  incubating  at  blood 
temperature,  but  he  found  that  by  this  method  the  parasites  were  quickly 
destroyed  and  that  no  development  occurred.  Using  the  same  method,  and 
incubating  at  270  C,  he  found  that  the  parasites  lived  for  several  days  and 
that  evidences  of  division  occurred,  but  no  flagellate  bodies  appeared.  However, 
upon  incubation  at  220  C.  he  found  that  the  parasites  multiplied  very  rapidly 
and  that  the  characteristic  flagellate  forms  developed  within  from  three  to  six 
days. 

The  following  procedure  will  be  found  to  result  in  success  if  carefully 
carried  out:  Prepare  some  normal  salt  solution  and  to  it  add  about  8  per 
cent,  of  sodium  citrate,  dissolving  thoroughly;  if  the  resulting  solution  is  not 
acid  in  reaction  it  should  be  made  very  slightly  so  by  the  addition  of  citric 
acid,  after  which  it  is  sterilized.  Several  test-tubes  of  small  caliber  should  be 
sterilized  after  stopping  them  with  cotton  wool,  and  a  reliable  glass  syringe,  to 


THE    BLOOD    PROTOZOA    OF    MAN.  419 

be  used  in  securing  the  blood,  should  be  sterilized  along  with  the  other  materials. 
A  patient  suffering  from  kala-azar,  in  whom  numbers  of  the  parasites  have 
been  demonstrated  by  microscopic  examination  of  smears  from  the  liver,  is 
selected,  and  the  liver  punctured,  using  the  sterile  syringe  and  observing  the 
most  careful  precautions  regarding  the  sterilization  of  the  skin  and  of  the  hands 
of  the  operator.  About  1  c.c.  of  blood,  or  more  if  the  blood  flow  freely,  is 
withdrawn  and  about  half  placed  in  one  culture  tube,  the  remainder  in  another, 
and  to  each  tube  about  1  c.c.  of  the  citrate  solution  is  added.  If  the  organisms 
are  not  very  numerous  it  is  preferable  to  add  all  of  the  blood  to  1  c.c.  of  the 
citrate  solution  in  one  tube.  After  gently  shaking  together  the  blood  and  the 
citrate  solution  the  tubes  are  placed  in  an  incubator  at  220  C.  (in  most  countries 
where  kala-azar  occurs  an  ice  incubator  will  be  necessary)  and  the  preparation 
examined  daily,  care  being  taken  not  to  infect  the  tubes,  as  such  infection 
inevitably  results  in  the  destruction  of  the  Leishman-Donovan  bodies. 

Rogers  calls  attention  to  the  following  important  points  which  should 
be  most  carefully  regarded  if  we  are  to  expect  success  with  the  culture  of 
Leishmania-donovani:  1.  The  temperature  used  for  incubation  should  be 
from  200  to  220  C,  as  very  marked  development  never  occurs  above  250  C. 
According  to  him,  an  exposure  for  even  a  short  time  to  a  temperature  above 
250  C.  results  in  the  destruction  of  the  parasites  in  the  culture.  The  minimum 
temperature  at  which  the  organisms  can  develop  is  about  17  °  C. 

2.  The  mixture  of  blood  and  citrate  solution  must  be  sterile  except  for 
the  Leishmania-donovani,  for  he  found  that  whenever  the  cultures  became 
contaminated  with  other  organisms  the  parasites  quickly  degenerated  and 
disappeared.  All  bacteria  are  inimical  to  successful  cultivation,  but  Rodgers 
found  that  the  staphylococci  especially  were  most  fatal  to  the  Leishman- 
Donovan  bodies  in  cultures. 

3.  The  medium  should  have  a  slightly  acid  reaction,  the  acidity  being 
secured  by  the  addition  to  the  infected  citrated  blood  solution  of  a  drop  or 
two  of  a  weak  citric  acid  solution.  Rogers  found  that  after  thus  modifying 
the  culture  media  the  flagellated  forms  appeared  more  rapidly  and  in  far  greater 
numbers,  and  that  the  development  was  much  more  uniform,  the  flagellates 
appearing  about  the  third  day. 

On  account  of  the  danger  attending  splenic  puncture,  it  is  preferable  to 
puncture  the  liver  in  order  to  obtain  material  for  culture. 

Transmission  and  Pathogenicity. — Aside  from  the  forms  observed  by 
Patton  in  a  species  of  bed-bug,  no  phases  in  the  development,  under  natural 
conditions,  of  Leishmania-donovani  outside  the  human  body  have  been 
observed,  nor  have  we  any  direct  experimental  evidence  that  this  parasite  will 
produce  kala-azar  upon  being  inoculated  in  man.  It  is  very  probable  that 
certain  forms  of  the  organisms  occur  in  natural  conditions  which  have  not  as 
yet  been  observed,  and  that  the  infective  stage  may  be  so  different  in  its 
morphology  from  the  known  developmental  stages  as  to  render  its  recognition 
impossible.     The  observations  of  Patton,  of  the  Indian  Medical  Service,  would 


420  THE    BLOOD    PROTOZOA    OF    MAN. 

appear  to  indicate  that  the  parasite  is  transmitted  by  the  bed-bug,  and  while  his 
observations  have  not  been  confirmed,  I  believe  that  he  has  shown  that  the 
parasite  can  undergo  development  within  an  insect  and  that  this  method  of 
transmission  is  the  most  probable  one  in  every  respect. 

The  development  in  cultures  of  flagellated  forms;  the  fact  that  develop- 
ment occurred  best  in  cultures  at  a  temperature  between  200  C.  and  220  C, 
and  that  the  medium  should  be  acid  in  reaction,  as  well  as  certain  well-known 
epidemiological  peculiarities,  suggested  to  Rogers  and  his  co-workers  that  the 
parasite  of  kala-azar  was  transmitted  to  man  by  a  biting  tick  or  insect.  Rogers 
endeavored  to  discover  the  organism  in  the  bodies  of  bed-bugs,  examining  no 
less  than  200  bugs,  but  was  unsuccessful.  Christophers  obtained  negative 
results  from  his  examinations  of  moscpiitoes  and  ticks,  and  the  work  of  a  few 
other  investigators  was  equally  unsuccessful  in  demonstrating  the  parasite 
within  the  body  of  the  insects.  In  1907,  Patton  published  a  preliminary 
note  describing  the  results  obtained  by  him  in  infecting  a  species  of  bed-bug 
with  Leishmania-donovani  by  feeding  experiments,  in  which  he  claimed  that  in 
the  stomach  of  the  infected  bugs  there  occurred  forms  similar  to  those  observed 
in  cultures.  Patton  has  continued  his  researches  in  this  direction  and  has,  I 
believe,  proven  that  in  bed-bugs  allowed  to  suck  the  blood  of  kala-azar  patients 
and  kept  at  a  temperature  of  220  C.  or  thereabouts,  flagellated  forms  develop 
like  those  observed  in  cultures  and  that  the  entire  process  of  development 
has  been  observed  in  blood  within  the  stomach  of  the  insect.  In  a  postscript 
to  his  original  paper  Patton  states  "  Since  wyriting  the  above  I  have  found  in  the 
bed-bug  (Cimex  macrocepJialus)  all  the  intermediate  stages  of  development 
and  numerous  fully  developed  flagellates  similar  to  those  seen  in  cultures 
of  splenic  blood,''  and  in  a  letter  to  Rogers,  quoted  by  the  latter  in  his  work, 
"Fevers  in  the  Tropics,"  he  says:  "There  is  no  shadow  of  doubt  that  the 
bed-bug  transmits  the  disease."  The  bed-bug  in  which  Patton  was  successful 
in  following  the  development  of  the  flagellated  stage  of  Leishmania-donovani  is 
Cimex  rotundatus  Signoret  {Cimex  macrocephalatns  Fieber). 

While  further  observation  will  probably  confirm  Patton's  work,  it  should 
be  noted  that  much  still  remains  to  be  done  before  we  possess  a  clear  under- 
standing of  the  exact  method  of  transmission  of  this  disease,  and  it  is  especially 
important  that  the  question  of  the  hereditary  transmission  of  the  infection  to 
bed-bugs  be  determined. 

Distribution  of  the  Leishman-Donovan  Bodies  in  Man. — These 
parasites  may  be  found  in  almost  every  organ  of  the  body,  but  are  most  numerous 
in  the  spleen,  bone-marrow,  and  liver.  The  pathology  of  kala-azar  and  the 
distribution  of  the  parasites  in  the  body  has  been  thoroughly  worked  out  by 
Leishman,  Marchand,  Statham,  Christophers,  Ledingham,  and  Manson, 
and  the  occurrence  of  the  parasites  in  the  blood  has  been  studied  especially 
by  Laveran,  Statham,  Christophers,  Rogers,  Donovan,  and  James.  From 
the  observations  of  these  investigators  it  has  been  proven  that  Leishmania- 
donovani  is  generally  found  within  the  cytoplasm  of  mononuclear  cells,  very 


THE    BLOOD    PROTOZOA    OF    MAN.  421 

seldom  being  observed  free  in  the  tissues  or  in  the  blood.  The  occurrence  of 
numerous  parasites  within  the  mononuclear  cells  appears  to  have  no  injurious 
action  until  the  entire  cytoplasm  is  filled  with  them,  when  the  nucleus  is  pushed 
to  one  side  and  the  cell  eventually  ruptures;  that  the  cell  itself  has  no  injurious 
action  upon  the  parasite  is  evidenced  by  the  fact  that  fission  occurs,  as  is 
shown  by  the  presence  in  most  of  the  cells  of  divisional  forms  in  all  stages  of 
division.  The  nature  of  the  mononuclear  cells  and  their  origin  has  been  shown 
by  the  studies  of  Christophers,  who  has  proven  that  they  are  endothelial  in 
character,  and  originate  from  the  walls  of  the  capillaries  and  lymphatics.  In 
other  words,  they  are  the  same  cells  which  act  as  "macrophages"  in  malaria, 
but  in  the  case  of  the  kala-azar  parasite  the  macrophage  is  unable  to  destroy 
the  organism,  as  it  does  in  malaria.  Christophers  has  shown  that  these  cells, 
crowded  with  Leishmania-donovani,  are  most  common  in  the  spleen  and  in  the 
bone-marrow,  but  they  have  also  been  found  in  the  liver,  mesenteric  glands, 
intestinal  ulcers,  lungs,  kidneys,  in  the  lymphatic  glands,  in  the  arachnoid,  and 
in  ulcerations  of  the  skin  and  skin  eruptions  in  kala-azar  patients.  In  fact,  the 
parasite  may  be  said  to  invade  the  endothelial  cells  of  the  capillaries  and  the 
lymphatics  in  almost  every  portion  of  the  body,  but  especially  in  the  spleen,  bone- 
marrow,  and  liver. 

Leishman  considers  that  the  parasite,  after  invading  the  body,  is  taken  up 
by  the  endothelial  cells,  as  these  cells  are  well  known  as  active  phagocytes,  but 
it  would  appear  more  probable  that  the  parasites  themselves  invade  the  endothe- 
lial cells,  as  it  would  seem  that  they  multiply  in  man  only  within  these  cells. 
However  this  may  be,  it  is  proven  that  the  Leishman-Donovan  body  is  an 
intracellular  parasite  whose  host  cell  is  the  endothelial  cell  of  the  blood-vessels 
and  lymphatics. 

After  multiplication  of  the  parasite  has  progressed  for  a  certain  time  the 
cytoplasm  of  the  cell  becomes  filled  with  young  organisms,  which  distend  the 
host  cell  and  eventually  cause  its  separation  from  the  wall  of  the  blood-vessel  or 
lymphatic.  The  infected  cell  then  ruptures  or  degenerates  and  the  young 
parasites  are  again  taken  up  by  endothelial  cells  or  actually  invade  them,  when 
the  process  of  division,  detachment  of  the  endothelial  cell,  and  liberation  of  the 
parasites  is  repeated.  The  infection  is  spread  through  the  body  by  the  presence 
in  the  blood  and  lymph  of  free  parasites  and  infected  leucocytes,  the  larger  of 
which  lodge  in  the  capillaries  of  various  organs;  the  granular  matrix  in  which 
hundreds  of  the  parasites  are  commonly  observed  embedded  is  undoubtedly 
the  degenerated  cytoplasm  of  the  endothelial  cell  invaded  by  the  organism. 

In  the  spleen,  which  is  greatly  enlarged,  a  microscopical  examination  shows 
the  sinuses  filled  with  multitudes  of  mononuclear  cells  containing  Leishmania- 
donovani;  the  infected  cells  vary  in  size  and  are  much  more  numerous  in  some 
portions  of  the  sections  than  in  others,  while  the  Malpighian  corpuscles  are 
generally  free  from  the  infection.  In  the  liver  the  entire  process  of  infection  of 
the  endothelial  cell  and  its  subsequent  detachment  from  the  wall  of  the  capillary 
may  be  easily  studied,  the  walls  of  the  portal  capillaries  being  covered  with  cells 


422 


THE    BLOOD    PROTOZOA    OF    MAN. 


containing  parasites,  the  cells  being  in  various  stages  of  detachment  from  the 
vessel  wall.  The  hepatic  capillaries  also  contain  many  large  mononuclear  cells 
filled  with  parasites.  In  the  bone-marrow  there  occur  multitudes  of  infected 
mononuclears,  showing  parasites  in  all  stages  of  division.  In  the  kidney  the 
endothelial  cells  showing  infection  are  those  of  the  smallest  capillaries,  especially 
those  of  the  glomerular  tufts,  and  the  parasites  have  never  been  demonstrated 
in  the  epithelial  cells  of  the  tubules.  The  parasites  have  never  been  found  in 
the  urine. 

The  Blood  in  Kala-azar. — The  observations  of  Donovan,  Christophers, 
James,  Laveran,  and  others  show  conclusively  that  the  Leishman-Donovan 
bodies  occur  in  the  peripheral  blood  and  that  in  many  cases  it  is  possible  to  find 


Fig.  27. — Leishmania  donovani  contained  within  a  large  endothelial  cell.     (Note  the  large 

number  of  the  parasites.)     Photomicrograph  from  a  splenic  smear  of  a  patient  suffering  from 

kala-azar,  kindly  sent  the  author  by  Dr.  Leishman,    X  1000. 


them  in  this  fluid.  Donovan  has  reported  finding  the  parasites  in  75  per  cent,  of 
his  cases  in  the  peripheral  blood  while,  according  to  Rogers,  Patton  was  able  to 
find  them  by  a  blood  examination  in  even  a  larger  proportion  of  advanced  cases. 
In  the  peripheral  blood  the  parasites  occur  within  the  leucocytes,  chiefly  the 
polynuclears  and  large  mononuclears.  Laveran  and  Mesnil  and  Donovan  have 
reported  the  occurrence  of  the  parasite  within  the  red  blood-corpuscles,  but 
their  observations  have  not  been  confirmed,  and  it  is  probable  that  parasites 
lying  upon  but  not  within  the  red  corpuscles  were  really  observed  by  these  in- 
vestigators, as  numerous  workers  have  reported  instances  of  this  character.  It 
has  been  found  that  the  parasites  appear  in  the  blood  most  frequently  during 
the  latter  stages  of  the  disease  and  that  repeated  examinations  of  the  blood  in 


THE    BLOOD    PROTOZOA    OF    MAN.  423 

new  infections  almost  invariably  result  negatively  so  far  as  the  presence  of   the 
parasite  is  concerned. 

Certain  changes  are  produced  in  the  blood  by  Leishmania-donovani  which 
are  of  interest  and  importance  from  a  diagnostic  standpoint.  In  advanced 
cases  there  is  marked  anaemia,  the  red  blood  count  being  reduced  to  from 
2,500,000  to  2,000,000  per  cu.  mm.  the  haemoglobin  being  reduced  in  propor- 
tion, while  there  is  a  marked  leucopenia,  the  white  cells  numbering  from  1,000 
to  5,000  per  cu.  mm.  The  most  characteristic  change  observed,  aside  from  the 
very  marked  leucopenia,  is  a  reduction  in  the  number  of  the  polynuclears  and 
eosinophiles,  and  a  large  increase  in  the  relative  proportions  of  the  large  mono- 
nuclears and  lymphocytes.  The  increase  in  large  mononuclears  is  of  greatest 
importance  from  a  diagnostic  standpoint,  according  to  Rogers,  but  it  should  be 
remembered  that  an  increase  occurs  in  these  cells  in  malaria,  trypanosomiasis, 
and  other  diseases,  so  that  it  cannot  be  considered  peculiar  to  kala-azar. 

Elimination  of  the  Parasites. — It  may  be  said  that  nothing  is  known 
with  certainty  regarding  the  elimination  of  Leishmania-donovani  from  the  body. 
They  have  never  been  demonstrated  in  any  of  the  excretions,  and  the  situation 
of  the  parasites  in  the  endothelial  cells  of  the  capillaries  in  the  kidneys,  and  their 
absence  from  the  renal  epithelium  or  the  cells  of  the  tubules  is  almost  certain 
proof  that  they  are  not  eliminated  through  the  kidneys.  The  occurrence  of 
the  parasites  in  the  intestinal  ulcers  and  in  eruptions  and  ulcerations  of  the  skin 
suggest  that  they  may  be  eliminated  in  the  faeces  or  through  the  skin,  but  they 
have  never  been  found  in  the  faeces,  and  as  the  ulcerations  of  the  skin  are  not  of 
constant  occurrence  it  is  not  probable  that  the  parasites  are  naturally  eliminated 
in  this  manner.  When  haemorrhages  occur,  which  are  not  infrequently 
observed  in  this  disease,  the  parasites  may  be  found  in  the  blood,  and  it  may  be 
that  this  is  one  method  of  elimination.  The  bites  of  insects  furnish  the  most 
probable  method  by  which  the  parasites  leave  man,  and  the  observations  of 
Patton,  already  referred  to,  would  appear  to  indicate  that  the  bed-bug  is  the 
intermediate  host  of  Leishmania-donovani. 

Demonstration  of  Leishmania-donovani. — As  the  diagnosis  of  kala- 
azar  rests  upon  the  recognition  of  Leishmania-donovani  in  the  blood  or  tissues, 
the  methods  available  for  its  demonstration  require  careful  consideration. 
The  parasite  is  most  easily  recognized  in  stained  specimens,  and  for  staining  the 
method  of  Wright,  of  Leishman,  and  the  Giemsa  stain,  described  in  the  section 
upon  malaria,  are  suitable.  Wright's  stain  is  very  satisfactory  and  I  believe  will 
be  found  most  useful,  but  Leishman's  method  is  excellent  and  is  the  one  which 
has  been  most  frequently  employed  for  the  demonstration  of  this  organism. 
The  Giemsa  stain  gives  good  results,  but  is  more  complicated  and  requires 
greater  care  in  order  to  secure  good  specimens. 

The  organisms  may  be  demonstrated  in  stained  smears  secured  from  the 
spleen  or  liver  by  puncture  or  in  smears  of  the  peripheral  blood.  On  account 
of  the  danger  of  splenic  puncture,  the  specimen  should  be  preferably  obtained 
from  the  liver,  the  utmost  precautions  being  exercised  as  regards  asepsis  of  the 


424  THE    BLOOD    PROTOZOA    OF    MAN. 

skin,  the  instrument  used,  and  the  hands  of  the  operator.  The  abdomen  should 
be  tightly  supported  by  a  bandage  and  the  patient  cautioned  against  jumping 
when  he  feels  the  sting  of  the  needle;  the  latter  should  be  a  long  hypodermic 
needle  having  a  very  sharp  point  and  not  too  fine  a  caliber.  It  should  be 
remembered  that  it  is  not  necessary  to  secure  much  of  the  material  for  examina- 
tion and  that  if  we  secure  only  blood  the  examination  will  probably  result 
negatively,  as  it  is  the  pulp  of  the  liver  or  spleen  which  will  give  the  best  results 
in  examination. 

The  examination  of  the  peripheral  blood  should  be  made  in  every  suspected 
case,  but  it  is  only  in  those  showing  high  fever  or  in  advanced  cases  that  we  can 
expect  to  find  the  parasite.  A  one-twelfth  inch  immersion  lens  should  be  used 
and  every  leucocyte  carefully  examined,  and  several  hundred  should  be  inspected 
before  the  result  is  recorded  as  negative.  The  examination  of  the  peripheral 
blood  will  generally  result  in  the  demonstration  of  the  parasite  in  advanced 
cases  when  there  is  high  temperature,  but  little  can  be  expected  from  it  in  the 
early  stages  of  the  disease,  and  thus  it  cannot  be  relied  upon  as  a  method  of 
diagnosis  in  such  cases.  To  facilitate  the  finding  of  the  parasites  in  the  periph- 
eral blood,  from  i  to  5  c.c.  of  blood  may  be  taken  from  a  vein,  added  to  a  centri- 
fuge tube  containing  a  little  sodium  citrate  solution  to  prevent  clotting,  and 
thoroughly  centrifuged,  after  which  specimens  are  prepared  from  the  upper 
portion  of  the  layer  of  cells.  Leishman  recommends  this  method,  but  Rogers 
states  that  he  has  not  been  able  to  demonstrate  the  organism  by  its  use.  It 
deserves  a  more  extended  trial.  The  presence  in  leucocytes  or  mononuclear 
(endothelial)  cells  of  bodies  possessing  a  capsule,  a  spherical  or  oval  mass  of 
chromatin,  and  a  rod-like,  much  smaller,  chromatin  mass,  the  entire  organism 
being  about  the  size  of  a  blood  platelet,  is  conclusive  as  to  the  presence  of  Leish- 
man ia  dcnovani,  when  such  cells  are  obtained  frcm  the  organs  or  peripheral 
blood  of  patients  suffering  from  fever. 

Leishmania  tropica  and  Leishmania  infantum. — Because  of  their  mor- 
phological resemblance  to Leishmania-dcnovani,  it  is  necessary  to  mention  briefly 
two  other  organisms  occurring  in  man  belonging  to  the  genus  Leishmania;  i.e., 
Leishmania  tropica,  discovered  by  Wright  in  the  granulation  tissue  cells  of 
oriental  sore  (tropical  ulcer)  and  Leishmania  infantum,  discovered  in  infants 
suffering  from  splenic  anaemia  by  Pianese  and  Nicolle.  Morphologically, 
these  organisms  are  indistinguishable  from  the  Leishman-Donovan  body,  but 
that  they  are  distinct  species  is  proven  by  the  pathological  lesions  produced  by 
them. 

Nicolle,  in  1908,  produced  splenic  anaemia  in  dogs  by  inoculating  them 
with  tissue  from  cases  of  splenic  anaemia,  and  cultivated  the  organisms  from 
the  experimental  animals  on  blood-agar,  flagellate  forms  developing  in  the 
cultures  like  those  of  the  Leishman-Donovan  body.  He  was  not  able  to  re- 
produce the  disease  by  inoculation  of  these  cultures,  but  Novy  in  the  same  year 
was  successful  in  producing  the  disease  in  a  dog  by  the  inoculation  of  cultures 
containing    numerous    flagellate   forms  obtained  from  Nicolle.     The  results 


THE    BLOOD    PROTOZOA    OF    MAN.  425 

obtained  by  Novy  prove  beyond  question  that  the  flagellate  forms  of  Leishmania 
infantum,  when  inoculated  into  dogs,  produce  a  disease  identical  with  infantile 
splenic  anaemia,  and  that  the  forms  found  in  the  dog's  tissues  are  morphologic- 
ally indistinguishable  from  the  forms  of  Leishmania-donovani  observed  in  man. 
His  results  also  prove  that  the  flagellate  forms  revert  to  forms  usually  observed 
in  man,  and  that  these  forms,  when  cultivated,  develop  typical  flagella,  as  he  was 
able  to  show  that  in  cultures  of  the  infected  dog's  blood  made  from  the  spleen, 
liver  and  bone-marrow  there  developed  "enormously  rich  cultures  of  the 
typical  flagellate  forms."  The  importance  of  the  work  of  Novy  in  its  relation 
to  the  life  history  of  Leishmania  donovani  cannot  be  over-estimated,  and  it  will 
indeed  be  surprising  if,  with  the  light  which  his  studies  have  thrown  upon  the 
subject,  we  are  unable  to  solve  the  problem  of  the  transmission  of  tropical 
spleno-megaly  or  kala-azar. 

Literature    upon   the    Leishman-Donovan    Bodies.     Leishmania-donovani. 

1897.  Rogers,  Leonard.      Report  on  Kala-azar. 

1898.  Giles.      The  Etiology  of  Kala-azar.      Ind.  Med.  Gaz.,  p.  1. 

1899.  Ross,  Ronald.      Report  on  the  Nature  of  Kala-azar. 

1899.     Rogers,  Leonard.     The  Diagnostic  and  Prognostic  Value  of  the  Leu- 

copenia  of  Cachexial  Fever  and  Kala-azar.      Brit.  Med.  Jour.,  Apr.   1. 
1902.      Bentley.      Epidemic  Malta  Fever  in  Assam,  etc.     Ind.  Med.  Gaz.,  p.  379. 

1902.  Rogers,  Leonard.  Note  on  the  Serum-reactions  and  the  Temperature 
Curve  in  Chronic  Malaria,  including  Kala-azar.      Ind.  Med.  Gaz.,  p.  377. 

1903.  Leishman.  On  the  Probability  of  the  Occurrence  of  Trypanosomiasis 
in  India.      Brit.  Med.  Jour.,  vol.  i,  p.   1252;  vol.  ii,  p.   1376. 

1903.      Ross,  Ronald.      Note   on  the    Bodies   Recently  Described  by  Leishman 

and   Donovan.      Brit.    Med.   Jour.,  vol.  ii,  p.   1261  and    1401,  Nos.  2237 

and  2239. 
1903.      Ross,  R.     A  New  Parasite  of  Man.     Thompson- Yates  Lab.  Reports,  vol. 

v,  p.  79. 
1903.      Donovan.      On   the   Possibility   of  the   Occurrence   of  Trypanosomiasis 

in  India.      Brit.  Med.  Jour.,  vol.  ii,  p.  59. 
1903.      Wright,  J.  H.      Protozoa  in  a  Case  of  Tropical  Ulcer  (Delhi  Boil).      The 

Jour,  of  Med.  Research,  vol.  x,  No.  3,  p.  472. 

1903.  Laveran  et  Mesnil.  Sur  un  protozoaire  noveau  (Piroplasma  Donovani) 
parasite  d'une  fievre  de  l'lnde.  Compt.  Rend.  Acad,  des  Sci,  Paris,  T. 
137,  No.  33,  pp.  957-961. 

1904.  Leishman.  The  Nature  of  the  Leishman-Donovan  Body.  Brit.  Med. 
Jour.,  vol.  ii,  No.  2270,  p.  29. 

1904.  Idem.  Discussion  on  the  Leishman-Donovan  Body.  Brit.  Med.  Jour., 
vol.  ii,  No.  2281,  p.  642. 

1904.  Idem.  Note  on  the  Nature  of  the  Parasites  Found  in  Tropical  Spleno- 
megaly.     Brit.   Med.  Jour.,   vol.  i,  p.  303. 

1904.  Leishman.  Notes  upon  the  Further  Investigation  of  the  Parasites  of 
Kala-azar  and  Delhi  Boil.      Jour.  R.  A.  Med.  Corps,  vol.  iii,  p.  287. 

1904.  Idem.  A  Method  of  Producing  Chromatin  Staining  in  Sections.  Jour,  of 
Hyg.,  vol.  iv,  No.  3,  p.  434. 

1904.  Manson  and  Low.  The  Leishman-Donovan  Body.  Brit.  Med.  Jour., 
vol.  i,  p.  1251. 


426  THE   BLOOD    PROTOZOA   OF   MAN. 

1904.      Idem.      The  Leishman- Donovan  Body  and  Tropical  Splenomegaly.      Brit. 

Med.  Jour.,  vol.  i,  p.  183. 
1904.      McFarland,   J.      The    Leishman-Donovan    Blood   Parasites.      American 

Medicine,  vol.  vii,  No.  23,  p.  888. 
1904.      Rogers,  Leonard,     Cachexial  Fever  in  India  Associated  with  Cunning- 
ham-Leishman-Donovan  Bodies.      Brit.  Med.  Jour.,  vol.  i,  p.   645. 
1004.      Idem.      Leishman-Donovan    Bodies   in    "Malarial  Cachexia"  and  Kala- 

azar.      Brit.  Med.  Jour.,  vol.  i,  p.  1249. 
1904.      Idem.      Preliminary  Note  on  the  Development  of  Trypanosoma  in  Cul- 
tures of  the  Cunningham-Leishman-Donovan  Bodies  of  Cachexial  Fever 

and  Kala-azar.     Lancet,  vol.  ii,  July,  23. 
1904.      Idem.      On  the  Development  of  Flagellated  Organisms  (trypanosomes) 

from  the  spleen  protozoic  parasites  of  Cachexial  Fevers  and  Kala-azar. 

Quart.  Jour.  Mocro.  Sci.,  vol.  xlviii,  Part  iii,  November. 
1904.      Donovan,  C.      Human  Piroplasmosis.      Lancet,  vol.  ii,  p.  744,  and   Brit. 

Med.   Jour.,   vol.   i,   p.    651. 
1904.      Idem.      Piroplasmosis.      A    History   of   the    Discovery   of   the    Donovan 

Bodies  in  Madras.      Ind.  Med.  Gaz.,  p.  321. 
1904.     Christophers,  S.  R.     A  Preliminary  Report  upon  a  Parasite  Found  in 

Persons  Suffering  from  Enlargement  of  the  Spleen  in  India.      Sci.  Men. 

Med.  and  San.  Depts.  Govt,  of  India,  N.  S.,  N.  8,  Calcutta. 
1904.      Idem.      On  a  Parasite  found  in  Persons  suffering  from  Enlargement  of  the 

Spleen  in  India.      Sci.  Mem   Med.  and  San.  Depts.,  Govt,  of  India,  No.  2. 
1904.      Idem.      Tropical  Splenomegaly  and  Oriental  Sore.      Brit.  Med.  Jour.,  vol. 

",  P-  655. 
1904.     Phillips,  L.      Note  on  the  Occurrence  of  the  Leishman-Donovan  Body 

in  Arabia  and  Egypt.  Brit.  Med.  Jour.,  vol.  ii  ,  p.  657. 
1904.      Castellani,   A.      Leishmania   Donovani   in   Ceylon.      Brit.    Med.  Jour., 

vol.  ii,  p.  656. 
1904.      Bentley,  A.      A  Short  Note  on  the  Parasite  of  Kala-azar.      Ind.  Med. 

Gaz.,  p.  81. 
1904.      Idem.      Notes  upon  Kala-azar  and  the  New  Parasite.      Brit.  Med.  Jour., 

vol.  ii,  p.  453. 
1904.      Laveran.      Piroplasma    donovani    en    Tunisis    d'apres    nue    observation 

de  Cathoire.      Bull,  de  l'Acad.  de  Med.  Seance  des  22  Mars. 
1904.      Laveran  et  Mesnil.      Nouvelles  observations  sur  Piroplasma  donovani 

Compt.   Rend.   Acad.   des.   Sci.,   Tome   138,  p.    187. 
1904.      Blanchard,  R.      Note  Critique  sur  les  corpuscles   de    Leishman.  Rev. 

de  Med.  et  d'hyg  tropicales,  p.   37. 
1904.      Neave,    S.      Leishmania    donovani    in    the    Soudan.    Brit.    Med.    Jour., 

vol.  i,  p.  12  52. 
1904.      Ruata,  G.  R.      Kala-azar  or  Tropical  Splenomegaly.    Jour  of  Trop.  Med., 

Nov.  15,  p.  350. 

1904.  Chatterjee,  G.  C.  Development  of  the  Flagellated  Stage  of  Leishman- 
Donovan  Bodies.      Lancet,  vol.  ii. 

1905.  Idem.  The  Cultivation  of  Trypanosoma  out  of  the  Leishman-Dono- 
van Body  by  the  Method  of  Capt.  L.  Rodgers.      Lancet,  vol.  i,  p.  16. 

1905.  Rogers,  L.  The  Conditions  affecting  the  Development  of  Flagellated 
Organisms  from  Leishman-Donovan  Bodies,  and  Their  Bearing  upon  the 
Probable  Mode  of  Infection.      Lancet,  vol.  i,  p.   1848. 

1905.  Statham,  J.  B.  C.  Preliminary  Note  on  the  Cultivation  of  the  Leishman 
Body.      Jour.   R.  A.   Med.  Corps,  vol.  iv,  January. 


THE    BLOOD    PROTOZOA    OF    MAN.  427 

1905.      Idem.      A  case  of  Kala-azar.      Jour.  R.  A.  Med.  Corps,  vol.   v,  Aug.  and 

Sept. 
1905.     Christophers,   S.    R.     On  a  Parasite  Found  in  Persons  Suffering  From 

Enlargement   of  the   Spleen  in   India.      Third   Report. 
1905.     James,    S.    P.      On    Kala-azar,    Malaria,    and    Malarial   Cachexia.      Sci, 

Mem.  Officers  Med.  and  San.  Depts.  Govt.  India,  N.  S.,  No.   19. 
1905.      Leishman    and    Statham.     The   Development   of  the   Leishman    Body 

in  Cultivation.     Jour.  R.  A.  Med.  Corps,  vol.  iv,  March. 
1905.      Manson,  Sir  P.      Notes  on  Two  Cases  of  Febrile  Tropical  Splenomegaly, 

etc.,  Brit.  Med.  Jour.,  Nov.  11. 
1905.     Rogers,  L.     The  Diagnostic  and  Prognostic   Value  of  the   Leucopenia 

of  Cachexial  Fever  and  Kala-azar.      Brit.   Med.  Jour.,  April  1. 

1905.  Childe,  L.  F.  The  First  Case  of  Leishman- Donovan  Disease  in  a  Euro- 
pean in  Bombay.      Ind.  Med.  Gaz.,  p.  447. 

1906.  Rogers,  L.  Further  Work  on  the  Development  of  the  Herpetomonas 
of  Kala-azar  and  Cachexial  Fever  from  Leishman-Donovan  Bodies. 
Proc.     Royal  Society,  vol.  lxxvii,  p.  284. 

1907.  Idem.  Milroy  Lectures  on  Kala-azar.  Abstracts  in  Brit.  Med.  Jour., 
vol.  i,  and  Lancet,  vol.  i. 

1907.  Patton,  W.  S.  Preliminary  Report  on  the  Development  of  the  Leish- 
man-Donovan Body  in  the  Bed-bug.  Sci.  Mem.  Med.  and  San.  Depts. 
Govt,  of  India,  N.  S.,  No.  27. 

1907.  Leishman.  Kala-azar,  in  System  of  Medicine,  Allbutt  and  Rolleston, 
vol.  ii,  Part  ii,  p.  226,  London.  Also  article  on  Kala-azar,  in  Memse's 
"  Handbuch  der  Tropenkrankheiten,"  Bandiii,  Halbbandii,  Leipzig,  1906. 

1907.  Manson,  Sir  P.  Kala-azar,  in  "Tropical  Diseases,"  4th  Ed.,  p.  178, 
London  and  New  York. 

1908.  Lyons,  I.  P.  Kala-azar,  in  Osier's  "Modern  Medicine,"  vol.  iv,  Phila- 
delphia, p.  770. 

1908.      Rogers,  L.     Fevers  in  the  Tropics,  p.  31,  London. 


CHAPTER  II. 

Trypanosoma  Gambiense    (Trypanosoma  Ugandense). 

Trypanosoma  gambiense  is  a  protozoan  parasite  of  the  blood,  occurring 
in  Africa,  and  causing  the  peculiar  disease  known  as  "sleeping  sickness." 
In  the  early  stages  of  the  disease  the  parasite  is  found  in  the  blood  and  lym- 
phatic glands,  and,  after  the  development  of  typical  symptoms,  in  the  cerebro- 
spinal fluid  as  well  as  in  the  blood  and  the  lymphatic  glands. 

Trypanosomes  are  probably  the  most  widely  distributed  of  all  protozoan 
parasites,  being  found  in  mammals,  birds,  reptiles,  batrachians,  fishes,  and 
insects.  To  Valentin,  of  Berne,  belongs  the  credit  of  the  discovery  of  the 
trypanosomes,  a  species  of  which  he  found  in  the  blood  of  trout,  but  it  was 
not  until  Dutton's  discovery  of  a  trypanosome  in  the  blood  of  man  in  1901  and 
the  subsequent  work  of  Castellani,  Bruce,  and  Nabarro,  proving  this  organism 
to  be  the  cause  of  sleeping  sickness,  that  the  trypanosomes  were  considered  of 
importance  in  human  pathology. 

Historical. — In  1841,  Valentin  discovered  and  described  the  first  trypano- 
some, a  parasite  of  the  trout  (Salmo  fario),  and  his  discovery  was  followed  by 
papers  relating  to  similar  organisms,  found  in  the  blood  of  the  frog,  by  Grube 
and  Gluge  (1842-1843),  the  former  author  first  applying  the  generic  term 
"trypanosoma"  to  these  organisms.  In  1845,  Gros  found  a  trypanosome 
in  the  blood  of  the  field  mouse  and  mole,  and  in  1850,  Chaussat,  and  in  1871, 
Ray  Lankester,  discovered  trypanosomes  in  the  blood  of  batrachians.  Interest 
in  these  organisms  was  renewed  in  1871,  by  Lewis,  who  found  that  a  trypano- 
some was  a  common  parasite  of  the  blood  of  rats  in  India,  and  his  observations 
were  very  soon  confirmed  by  workers  in  other  parts  of  the  world,  All  of  the 
trypanosomes  discovered  up  to  and  including  Lewis's  trypanosome,  were  non- 
pathogenic, but  in  1880,  Evans  discovered  a  trypanosome  in  the  blood  of 
horses  suffering  from  "surra,"  which  he  proved  experimentally  to  be  the  cause 
of  that  disease.  The  discovery  of  Evans  was  followed  in  1894  by  that  of  Rouget, 
who  found  another  trypanosome  in  the  blood  of  a  horse  suffering  from  dourine 
(mal  du  coit);  of  Bruce,  of  the  trypanosoma  of  nagana;  of  Elmassion,  of  the 
trypanosome  of  mal  de  caderas;  and  of  Theiler,  of  the  trypanosoma  of  galziekte 
or  gall-sickness  of  cattle  in  the  Transvaal. 

Until  1902,  the  date  of  the  discovery  of  the  trypanosome  of  Theiler,  it  was 
supposed  that  the  trypanosomes  were  parasites  of  the  lower  animals  only,  but 
the  observations  of  Dutton  and  Todd  and  of  Castellani,  Bruce  and  Nabarro,  in 
1902  and  1903,  conclusively  proved  that  there  occurred  in  man  a  pathogenic 

428 


THE    BLOOD    PROTOZOA    OF    MAN.  429 

trypanosome  of  the  greatest  importance  because  of  the  fatal  disease  of  which  it 
was  the  etiological  factor. 

The  trypanosome  of  man  is  the  cause  of  sleeping  sickness,  a  disease  first 
described  by  Winterbottom  in  1803  as  occurring  among  the  negroes  along  the 
West  Coast  of  Africa.  On  account  of  its  peculiar  symptoms  this  disease  has 
always  attracted  a  great  deal  of  attention,  and  many  efforts  were  made  to  de- 
termine its  etiological  organism,  many  bacteria  having  been  described  as  con- 
cerned in  its  production.  Marchoux,  Bettencourt,  and  Castellani  were  among 
the  most  earnest  students  of  the  disease  and  all  described  some  bacterium  as  the 
causative  factor.  Manson  for  a  long  time  considered  that  sleeping  sickness  was 
due  to  Filaria  perstans,  because  this  organism  was  met  with  so  often  in  the  blood 
of  those  suffering  from  the  disease,  but  the  fact  that  Filaria  perstans  occurs  in 
many  regions  where  sleeping  sickness  is  unknown  and  that  many  victims  of 
sleeping  sickness  are  not  infected  with  this  parasite,  conclusively  proved  that 
the  filaria  had  no  relation  to  the  disease. 

In  1 901,  Forde  observed,  in  the  blood  of  a  European  in  the  hospital  at 
Bathurst,  Gambia,  minute,  actively  motile,  worm-like  bodies,  the  nature  of 
which  he  was  unable  to  determine,  but  Dutton,  who  examined  the  blood  of  the 
same  patient  in  December,  1901,  recognized  the  bodies  as  trypanosomes,  and 
gave  the  name  Trypanosoma  gambiense  to  the  organism.  The  occurrence  of 
this  organism  in  the  blood  of  certain  patients  suffering  from  fever  was  con- 
firmed by  Dutton  and  Todd,  Manson,  Broden,  Brumpt,  and  Baker  in  1903, 
and  Maxwell-Adams  in  the  same  year  suggested  that  the  organism  might  be 
the  cause  of  sleeping  sickness. 

In  1903,  Castellani,  while  engaged  in  examining  the  cerebrospinal  fluid  of 
negroes  suffering  from  sleeping  sickness,  discovered  that  a  large  proportion  of 
them  showed  a  trypanosome  in  this  fluid,  which  he  considered  a  different 
species  from  Trypanosoma  gambiense,  and  which  he  called  Trypanosoma 
ugandense,  a  name  afterward  amended  to  Trypanosoma  castellani,  by  Kruse. 
The  discovery  of  Castellani  was  confirmed  by  Bruce  and  Nabarro  at  once; 
they  found  the  parasite  in  the  cerebro-spinal  fluid,  in  every  one  of  thirty-eight 
cases  examined  and  in  twelve  of  them  in  the  peripheral  blood.  These  authors 
concluded,  that  the  trypanosome  was  the  cause  of  the  disease,  and  their  researches 
were  confirmed  by  Greig,  Brumpt,  Dutton,  Todd,  Broden,  and  Christy. 

For  some  time  the  trypanosome  found  in  sleeping  sickness  and  that  found 
in  patients  suffering  from  irregular  fever  (Trypanosoma  gambiense  and  Trypano- 
soma ugandense)  were  thought  to  be  different  species,  and  Castellani  stated 
that  well-marked  morphological  differences  existed  between  them,  but  the 
observations  of  Bruce,  Nabarro,  Greig,  Dutton,  Todd,  and  Christy  proved 
that,  without  doubt,  the  trypansoma  found  in  sleeping  sickness,  and  discovered 
by  Castellani,  was  identical  with  that  found  in  fever  cases,  and  discovered  by 
Dutton  and  Forde.  The  later  observations  of  Thomas  and  Linton,  Laveran, 
Thomas  and  Breinl,  and  Gray  and  Tulloch  upon  the  pathogenic  lesions 
caused   in   animals  by  these  organisms  confirm  the  observations  based  upon 


430  THE    BLOOD    PROTOZOA    OF    MAN. 

morphology,  and  it  is  now  generally  accepted  that  Trypanosoma  gambiense  and 
Trypanosoma  ugandense  are  identical  and  that  the  organism  should  be  known 
as  Trypanosoma  gambiense. 

The  earliest  symptoms  of  sleeping  sickness  are  not  those  of  lethargy,  but 
are  characterized  by  fever,  swelling  of  the  lymphatic  glands,  and  skin  eruptions, 
and  it  is  during  this  stage  that  the  trypanosomes  are  found  in  the  peripheral 
blood  and  in  the  gland  juices,  while  they  are  found  in  the  cerebrospinal  fluid 
only  after  the  onset  of  the  symptoms  typical  of  sleeping  sickness:  languor, 
gradually  developing  sleepiness,  tremor,  and  coma.  In  other  words,  sleeping 
sickness  is  merely  the  termination  of  trypanosoma  infection  or  trypanosomiasis. 

Geographical  Distribution. —  Trypanosoma  gambiense  is  confined,  as 
regards  its  geographical  distribution,  to  certain  parts  of  Equatorial  Africa. 
It  is  found  most  frequently  along  the  West  Coast,  in  Gambia,  Uganda,  the 
Congo  basin,  Sierra  Leone,  Liberia,  Upper  Guinea,  the  Ivory  Coast,  and 
Yatenga.  It  is  also  found  in  South  Angola  (Wellman),  the  Upper  Niger, 
Lagos,  Togo,  the  Cameroon  (Ziemann),  Angola,  Portuguese  West  Africa, 
French  Congo,  the  Congo  Free  State,  German  East  Africa  (Ahlbory),  and  in 
the  Nile  Valley.  The  parasite  is  found  along  the  banks  of  lakes  and  rivers, 
and  the  extension  of  commerce  and  means  of  travel  in  Africa  has  resulted  in 
the  introduction  of  the  parasite  into  many  localities  where,  until  quite  recently, 
it  was  unknown.  The  rapid  extension  of  sleeping  sickness  throughout  the 
river  valleys  of  Africa  has  become  of  the  greatest  economical  importance,  as  the 
disease  is  invariably  fatal  and  has  already  caused  the  death  of  hundreds  of 
thousands  of  the  natives  of  the  infected  regions.  It  is  estimated  that  in  Uganda 
alone  more  than  100,000  deaths  have  occurred  from  infection  with  this  parasite 
during  the  six  years  from  1901  to  1907. 

Biological  Position. — There  is  no  doubt  regardng  the  biological 
position  of  Trypanosoma  gambiense.  In  1843,  Grube  established  the  genus 
Trypanosoma,  in  which  he  placed  the  trypanosome  of  the  frog,  and  in  which  all 
organisms  possessing  the  morphology  of  a  typical  trypanosome  must  be  placed. 
As  regards  its  generic  position,  therefore,  Trypansoma  gambiense  is  a  member 
of  the  genus  Trypanosoma.  As  regards  its  relation  to  the  Protozoa,  in  a 
wider  sense,  it  belongs  to  the  Mastigophora,  sub-class  Flagellata,  and  family 
Trypanosomatidae. 

General  Morphology  of  Trypanosomes. — It  is  necessary,  in  order  to 
understand  thoroughly  the  structure  of  Trypanosoma  gambiense,  to  consider  in 
detail  the  morphology  of  trypanosomes  in  general  and  their  biological  peculiari- 
ties. Laveran  and  Mesnil,  in  their  classical  work  upon  the  trypanosomes, 
state  that  "Several  mammalian  trypanosomes  resemble  one  another  so  closely 
that  it  is  impossible  to  distinguish  them  by  their  morphological  characters  alone. 
This  applies  to  the  trypanosomes  of  nagana,  surra,  dourine,  and  sleeping 
sickness."  It  will  thus  be  seen  that  a  study  of  the  morphology  of  the  trypano- 
somes, as  a  class,  is  of  importance  in  the  study  of  any  one  species  of  trypano- 
some, as  in  this  way  only  can  we  interpret  many  structural  phenomena  observed 


THE    BLOOD    PROTOZOA    OF    MAN.  43 1 

in  isolated  organisms  or  understand  the  significance  of  certain  biological  pro- 
cesses which  may  only  rarely  be  observed  in  the  organism  under  consideration. 

All  typical  trypanosomes  are  spindle-shaped,  and  possess  a  nucleus,  a 
centrosome  or  blepharoplast,  and  an  undulating  membrane  which  ends  in  a 
flagellum.  Among  zoologists  there  is  considerable  discussion  as  to  which  end 
of  the  trypanosome  the  flagellum  arises  from,  the  anterior  or  posterior.  Laveran 
and  Mesnil  consider  the  extremity  from  which  the  flagellum  arises  as  the 
anterior  extremity,  and  this  interpretation  is  accepted  by  most  authorities,  but 
Woodcock,  Sambon,  Manson,  and  others,  regard  the  flagellated  extremity  as 
posterior.  In  order  to  avoid  confusion  it  is  better,  as  suggested  by  Minchin, 
to  distinguish  the  two  extremities  of  the  body  of  the  trypanosome  as  the  flagellar 
and  anti flagellar  extremities,  respectively. 

A  trypanosome  presents  for  description  a  body,  a  nucleus,  a  blepharo- 
plast, an  undulating  membrane,  and  a  flagellum. 

The  body  is  more  or  less  spindle-shaped  in  all  but  cultural  forms,  some 
of  which  may  be  almost  spherical.  As,  however,  no  one  has  yet  succeeded 
in  cultivating  Trypanosoma  gambiense,  the  morphology  of  cultural  forms 
will  not  be  considered  in  this  summary  of  the  general  morphology  of  the 
trypanosomes.  Considerable  variation  exists  as  regards  the  shape  of  the 
organism,  even  in  individuals  of  the  same  species,  and  short,  blunt-ended 
forms  occur  together  with  slender,  pointed  organisms,  in  the  same  specimen 
of  blood.  The  shape  of  the  organism  may  also  differ  according  to  the  species 
of  animal  which  is  infected. 

The  flagellar  extremity  of  a  trypanosome  is  generally  longer  and  narrower 
than  the  antiflagellar  extremity,  and  may  be  pointed  or  slightly  rounded. 
A  careful  examination  will  demonstrate  that  in  nearly  every  case  it  is  continued 
for  a  little  distance  along  the  flagellum,  which  thus  does  not  start  abruptly 
from  the  body,  but  gradually,  as  a  continuation  of  the  undulating  membrane 
and  the  protoplasm  of  the  body. 

The  antiflagellar  extremity  varies  extremely  in  shape  in  various  species, 
in  individuals  of  the  same  species,  and  in  the  blood  of  the  same  animal.  Thus 
it  may  be  elongated  and  pointed,  short  and  blunt,  or  hemispherical  in  shape,  and 
in  Trypanosoma  gambiense  the  variation  is  often  very  marked. 

The  protoplasm  of  trypanosomes  stains  a  deep  blue  when  Wright's  method 
is  used  and  is  composed  apparently  of  fine  granules;  arranged  in  more  or  less 
irregular  masses.  This  arrangement  of  the  granules  causes  an  irregular 
staining  of  the  protoplasm,  some  areas  appearing  a  deep  blue,  while  others  are 
almost  unstained.  Chromatic  granules  are  present  in  some  organisms,  staining 
a  deep  violet,  and  irregularly  distributed  in  the  protoplasm.  These  granules 
may  be  of  some  service  in  determining  species,  but  cannot  be  greatly  relied 
upon  for  this  purpose.  The  body  is  not  surrounded  by  a  definite  membrane, 
so  far  as  we  have  been  able  to  determine.  The  protoplasm  surrounds  the 
nucleus  and  the  blepharoplast,  and  may  contain  one  or  more  vacuoles,  especially 
in  degenerating  organisms. 


432  THE    BLOOD    PROTOZOA    OF    MAN. 

The  nucleus,  which  stains  a  bright  crimson  or  violet,  with  Wright's  stain,  or 
any  modification  of  the  Romanowsky  method,  is  known  also  as  the  macronucleus 
or  trophonucleus;  it  is  much  larger  than  the  blepharoplast,  is  round  or  oval  in 
shape,  and  situated  at  or  near  the  center  of  the  body  of  the  organism.  In 
T.  lewisi  it  is  situated  in  the  flagellar  end,  and  is  of  diagnostic  importance. 
The  nucleus  is  composed  of  chromatin  granules  arranged  compactly  (the 
granules  varying  in  size),  and  connected  by  a  dimly  staining  nuclear  substance. 
The  nucleus  divides  amitotically. 

The  blepharoplast,  also  known  as  the  mieronucleus,  centrosome,  or  kincto- 
nucleus,  is  very  much  smaller  than  the  nucleus,  and  in  most  species  of  trypano- 
somes  is  situated  near  the  antiflagellar  extremity.  In  trypanosomes  undergoing 
division  the  blepharoplast  may  be  near  the  center  of  the  organism,  in  close 
relation  to  the  nucleus,  and  in  some  species  it  is  always  situated  in  this  region. 
It  generally  consists  of  a  small,  compact  mass  of  chromatin  granules,  staining 
a  deeper  purple  or  red  than  the  nucleus;  spherical  in  shape;  and  surrounded  by 
a  clear,  unstained  area,  oval  in  shape,  which  resembles  in  appearance  a  vacuole. 
It  measures  from  0.5  to  1  micron  in  diameter,  and  generally  stains  so  intensely 
that  the  separate  granules  of  chromatin  composing  it  are  invisible.  As  it 
usually  lies  near  the  antiflagellar  or  narrow  extremity  of  the  parasite,  it  often 
appears  to  extend  the  entire  width  of  the  organism,  but  careful  examination 
will  demonstrate  that  a  narrow  rim  of  protoplasm  surrounds  it,  if  the  vacuole 
mentioned  be  absent.     The  blepharoplast  divides  by  simple  fission. 

The  undulating  membrane  is  a  beautifully  curved  and  delicate  membrane 
extending  as  a  crest  or  ridge  for  a  variable  length  along  the  body  of  the  trypano- 
some.  It  varies  in  length  with  the  situation  of  the  blepharoplast  and,  as  in 
most  of  the  trypanosomes,  this  is  near  the  antiflagellar  extremity  the  undu- 
lating membrane  extends  along  the  greater  portion  of  the  body.  The  structure 
of  this  membrane  appears  similar  to  that  of  the  protoplasm  of  the  body,  but  its 
border  is  thickened  owing  to  the  flagellum  which  forms  it,  together  with  the 
protoplasm  of  the  membrane.  This  membrane  always  arises  opposite  the 
blepharoplast  on  the  lateral  surface  of  the  body,  and  extends  toward  the 
flagellar  extremity,  forming,  in  most  instances,  along  with  the  flagellum,  the 
flagellar  extremity  of  the  trypanosome.  The  number  of  curves  varies  with 
the  species  of  trypanosome  and  in  some  species  the  undulating  membrane 
is  thin  and  almost  straight.  The  presence  of  striations  in  the  undulating  mem- 
brane of -some  trypanosomes  has  been  reported  by  Prowazek  and  others,  but 
most  mammalian  trypanosomes  do  not  present  any  very  definite  structure  of 
the  membrane. 

The  flagellum  arises  from  the  blepharoplast,  is  continued  along  the  border 
of  the  undulating  membrane,  and  in  most  trypanosomes  extends  for  some 
distance  beyond  the  extremity  of  the  body,  or  undulating  membrane,  as  a 
free  flagellum.  In  organisms  which  show  a  vacuole  lying  in  contact  with  the 
blepharoplast  the  flagellum  appears  to  arise  from  the  border  of  this  vacuole, 
but  in  organisms  showing  no  vacuole  the  flagellum  is  observed  to  arise  directly 


THE    BLOOD    PROTOZOA    OF    MAN.  433 

from  the  blepharoplast.  Laveran  and  Mesnil  divide  the  flagellum  into  three 
portions:  the  root,  that  portion  extending  from  the  blepharoplast  to  the 
commencement  of  the  undulating  membrane;  the  intermediate  portion,  running 
along  the  edge  of  the  undulating  membrane;  and  the  free  portion,  forming  the 
free  flagellum  of  the  trypanosome.  The  thickness  of  the  flagellum  varies 
somewhat,  it  being  thickest  along  the  border  of  the  undulating  membrane  and 
thinnest  at  its  origin  and  its  free  extremity.  With  any  modification  of  the 
Romanowsky  stain  it  takes  a  dark  red  or  purple  color,  exactly  similar  to 
that  of  the  blepharoplast,  thus  proving  that  the  flagellum  is  composed  of 
chromatin.  Longitudinal  division  of  the  flagellum  occurs  during  multiplica- 
tion of  the  parasite  in  most  species  of  trypanosomes,  the  blepharoplast  first 
dividing,  followed  by  the  division  of  the  flagellum  along  its  entire  length. 
In  some  species  only  the  blepharoplast  divides  and  the  root  of  the  flagellum. 

Morphology  of  Trypanosoma  gambiense. — In  fresh  blood  Trypano- 
soma gambiense  may  be  easily  found  with  a  1/6  inch  objective,  appearing 
as  an  active,  spindle-shaped,  colorless  body,  forcing  its  way  among  the  corpuscles 
or  moving  in  a  jerky  manner  across  the  field  of  the  microscope.  Its  morphology 
cannot  be  satisfactorily  studied  in  fresh  specimens,  and  for  this  purpose  stained 
preparations,  using  some  modification  of  the  Romanowsky  stain,  should  be 
employed. 

Trypanosoma  gambiense  varies  considerably  in  length,  measuring  from 
16  to  30  microns  long  by  1.5  to  2.5  microns  wide,  the  longest  forms  being 
those  which  are  undergoing  division.  The  flagellum  originates  in  the  blepharo- 
plast, forms  the  edge  of  the  undulating  membrane,  and  is  continued  as  a  free 
flagellum  which  forms  from  one-quarter  to  nearly  one-half  the  total  length  of 
the  organism.  In  rare  instances  there  is  no  free  flagellum,  the  protoplasm  of 
the  body  and  of  the  undulating  membrane  extending  and  blending  with  the 
flagellum  for  its  entire  length. 

The  nucleus  is  oval  in  shape,  comparatively  large,  and  situated  near  the 
center  of  the  body  or  slightly  toward  the  antiflagellar  extremity ;  it  stains  deeply 
with  the  chromatin  stains. 

The  blepharoplast  is  situated  at  the  antiflagellar  extremity,  stains  a  deep 
purple,  and  is  composed  apparently  of  a  single  large  dot  of  chromatin.  An 
unstained  area  generally  surrounds  the  blepharoplast  but  according  to  Laveran 
and  Mesnil,  this  appearance  is  due  to  faulty  technic  in  preparing  the  specimen, 
and  it  is  undoubtedly  true  that  many  of  the  trypanosomes  do  not  present  this 
vacuole.  The  flagellum,  in  well  stained  specimens,  is  seen  to  arise  from  the 
blepharoplast,  being  intimately  connected  with  it  at  its  origin. 

The  antiflagellar  extremity  of  the  trypanosome  varies  in  shape,  being 
narrow  and  pointed  sometimes,  and  sometimes  rounded  and  broad.  It  is  evi- 
dent that  the  organism  possesses  the  power  of  altering  the  shape  of  this  ex- 
tremity, and  that  many  of  the  appearances  presented  in  stained  preparations 
are  caused  by  agonal  movements  of  the  parasite. 

The  flagellar  extremity  is  generally  pointed,  the  body  being  attenuated 
28 


434  THE    BLOOD    PROTOZOA    OF    MAN. 

gradually  until  it  becomes  blended  with  the  undulating  membrane  and  the 
flagellum. 

The  protoplasm  stains  a  delicate  blue  and  contains  chromatic  granules, 
which  vary  in  shape,  size,  and  number  in  individual  organisms. 

The  description  given  applies  to  the  average  of  parasites  observed,  but  it 
should  be  remembered  that  great  variations  occur  in  the  morphology  of  this 
trypanosome,  as  observed  in  stained  specimens,  some  of  them  due  to  errors  in 
technic,  and  others  representing  stages  in  the  development  of  the  parasite, 
with  which,  at  present,  we  are  unfamiliar.  Thus  we  often  observe  long, 
slender  organisms  and  short,  blunt  ones  in  the  same  specimen;  some  that  stain 
well  and  others  that  stain  with  difficulty;  some  in  which  the  nucleus  is  near  the 
center  and  others  in  which  it  is  near  the  flagellar  or  antiflagellar  extremity; 
some  in  which  the  blepharoplast  lies  within  a  vacuole,  and  others  in  which  the 
vacuole  is  absent.  Forms  also  occur  without  a  free  flagellum,  and  others  in 
which  the  undulating  membrane  is  rudimentary  or  even  absent,  while  the 
nucleus  and  blepharoplast  are  situated  in  a  nearly  spherical  body,  in  close  con- 
tact with  one  another.  In  some  chromatic  granules  are  absent  while  in  others 
they  are  present  in  great  numbers  and  are  of  large  size.  Many  trypanosomes 
are  observed  undergoing  degenerative  changes,  the  protoplasm  being  filled 
with  vacuoles  while  the  nucleus  and  blepharoplast  either  stain  very  faintly  or 
not  at  all,  the  free  flagellum  also  being  absent,  and  the  portion  forming  the 
border  of  the  undulating  membrane  staining  so  faintly  as  to  be  almost  invisible. 
In  most  instances  two  distinct  forms  of  Trypanosoma  gambiense  may  be 
distinguished  in  the  blood:  one,  slender,  and  having  a  free  flagellum  of  con- 
siderable length;  the  other,  short  and  broad,  and  having  a  short  free  flagellum. 
According  to  the  researches  of  Prowazek,  Luhe,  Zieman  and  Nocht,  it  is 
probable  that  the  long  slender  forms  are  males  and  the  short,  broad  forms 
females,  while  the  forms  which  are  intermediate  are  the  so-called  "indifferent 
forms"  which  are  not  sexual  in  nature. 

Multiplication. — In  the  blood  of  man  Trypanosoma  gambiense  multiplies 
by  binary  division,  the  blepharoplast  first  dividing  into  two,  followed  by  the 
nucleus,  the  flagellum,  and  the  protoplasm  of  the  body,  so  that  eventually  two 
trypanosomes  result.  As  it  has  been  proven  that  some  trypanosomes  undergo 
a  sexual  cycle  of  development  in  an  intermediate  host  (a  blood-sucking  inverte- 
brate in  all  the  species  so  far  investigated),  it  is  probable  that  Trypanosoma 
gambiense  also  has  an  intermediate  host  and  that  sexual  multiplication  occurs  in 
that  host,  but  at  the  present  time  we  are  ignorant  of  the  changes  occurring 
during  such  a  cycle,  although  we  know  that  the  parasite  is  transmitted  by 
Glossina  palpalis  and  others  species  belonging  to  the  same  genus. 

It  is  not  necessary  to  call  attention  here  to  the  work  of  Prowazek  on  the 
changes  occurring  in  Tr.  Icwisi  in  the  stomach  of  the  rat  louse  {Haematopimis 
spinulosis)  beyond  stating  that  he  was  able  not  only  to  demonstrate  various 
stages  of  development  of  this  trypanosome  in  the  louse,  but  also  to  prove  beyond 
question  that  this  louse  is,  in  fact,  the  intermediate  host  of  the  trypanosome, 


THE    BLOOD    PROTOZOA    OF    MAN. 


435 


sexual  forms  being  developed  in  the  gut  of  the  louse.  However,  while  the  inter- 
mediate host  of  Tr.  lewisi  is  undoubtedly  the  rat  louse,  we  have  no  conclusive 
evidence  that  Glossinapalpalis  is  the  intermediate  host  of  Trypanosoma  gambiense. 
The  observations  of  Koch  and  Gray  and  Tulloch  appeared  for  a  while  to 
indicate  that  this  trypanosome  underwent  sexual  development  in  the  stomach 
of  Gl.  palpalis,  but  the  careful  work  of  Novy  upon  the  trypanosomes  of  tsetse 
flies  proved  beyond  question  that  the  trypanosomes  studied  by  the  investigators 
mentioned  were  peculiar  to  tsetse  flies  and  had  no  relation  whatever  to  Trypano- 
soma gambiense.  In  a  later  paper  by  Minchin,  Gray,  and  Tulloch,  these 
authors  say,  "  We  are,  therefore,  now  convinced  from  the  results  of  these  numer- 
ous experiments  that  the  trypanosomes  found  in  the  freshly  caught  flies  have 
nothing  to  do  with  sleeping  sickness  and  are  not  developmental  stages  of  Tr. 
gambiense."  These  authors  also  found  that  flies  infected  with  this  trypano- 
some were  not  infective  after  48  hours,  and  while  they  describe  sexual  forms  in 
the  fly  they  are  the  same  that  occur  in  blood  films  from  man.     At  the  present 


a  bo 

Fig.  28. — Trypanosoma  gambiense. 
A,  Trypanosoma   gambiense,  after   Dutton.     B,  Trypanosoma   gambiense,    after    Liihe. 
C,  Trypanosoma  gambiense,  after  Liihe. 


time,  therefore,  there  is  no  evidence  that  the  tsetse-fly  is  the  intermediate  host 
of  Trypanosoma  gambiense,  but  that  this  insect  transmits  the  infection  directly, 
no  sexual  cycle  being  necessary  before  the  trypanosome  becomes  infective. 
This  does  not,  however,  preclude  the  existence  of  a  true  intermediate  host  for 
this  trypanosome.  The  observations  of  Salvin-Moore  and  Breinl  regarding  a 
resistant  form  of  Trypanosoma  gambiense  which  they  observed  in  infected  rats, 
have  not  as  yet  been  confirmed,  but  are  worthy  of  further  investigation.  In 
rats  infected  with  Trypanosoma  gambiense  they  observed  in  the  lungs,  bone- 
marrow,  and  spleen,  small  round  bodies,  consisting  of  protoplasm  and  nucleus, 
which  they  claim  are  derived  from  the  trypanosomes.  Under  favorable  condi- 
tions typical  trypanosomes  develop  from  these  bodies  and  multiply  as  usual. 
The  resistant  forms  only  develop  when  the  trypanosomes  begin  to  disappear 
from  the  peripheral  blood  of  the  rats.  These  observations  are  very  suggestive 
and  may  explain  the  persistence  of  trypanosome  infection  after  treatment  has 
resulted  in  causing  the  disappearance  of  the  parasites  from  the  blood. 


436  THE   BLOOD    PROTOZOA    OF   MAN. 

Cultivation. — Although  Novy  and  MacNeal  have  succeeded  in  cultivating 
certain  trypanosomes  upon  artificial  media,  and  their  work  has  been  confirmed 
by  numerous  other  investigators,  the  attempts  at  cultivation  of  Trypanosoma 
gambiense,  with  the  exception  of  the  partial  success  of  Gray  and  Tullock,  have 
met  with  failure.  Novy  and  MacNeal  have  succeeded  in  cultivating  Tr. 
lewisi,  Tr.  brucei,  and  Tr.  evansi,  as  well  as  other  trypanosomes  of  less  im- 
portance, and  it  was  hoped  that  by  following  their  methods  it  would  be  possible 
to  cultivate  the  parasite  of  sleeping  sickness,  but  little  success  has  attended  the 
efforts  of  these  who  have  endeavored  to  do  so,  for  while  it  has  been  possible 
to  keep  the  parasite  alive  upon  the  artificial  media  used,  multiplication  oc- 
curred in  but  one  experiment,  and  subcultures  could  not  be  obtained.  Thomas 
and  Breinl  used  chicken  and  veal  infusion  in  their  experiments,  to  which  was 
added  1  to  2  per  cent,  salt,  2.5  to  3.5  per  cent,  agar,  and  1  to  1.5  per  cent,  pep- 
tone. This  medium  was  prepared  and  added  in  the  proportion  of  two  to  one,  or 
three  to  two,  to  rabbit's  or  sheep's  blood,  the  rabbit's  blood  being  preferable. 
In  this  medium  the  trypanosomes  lived  for  from  10  to  40  days,  and  in  one  instance 
living  trypanosomes  were  found  after  50  days,  but  there  was  no  multiplication  of 
the  organisms,  and  sub-cultures  could  not  be  obtained. 

The  experiments  of  Gray  and  Tulloch  were  more  successful  in  that  multi- 
plication did  occur  in  their  tubes,  but  they  also  were  unable  to  obtain  sub- 
cultures. They  used  the  media  of  Novy  and  MacNeal  (agar),  adding  to  it  three 
times  the  volume  of  defibrinated  blood  from  the  dog. 

In  their  culture  tubes,  inoculated  from  the  blood  of  a  white  rat,  which  con- 
tained many  trypanosomes,  there  were  found  on  the  fifteenth  day  numerous 
organisms,  occurring  singly  and  in  groups,  many  of  which  were  undergoing 
division.  The  trypanosomes  were  longer  and  broader  than  those  observed  in 
the  blood  of  the  rat  and  of  man,  and  the  blepharoplast  was  placed  much  closer 
to  the  nucleus.  After  the  twentieth  day  the  trypanosomes  disappeared  from 
the  cultures,  which  became  greatly  contaminated  by  bacteria  of  various 
kinds. 

Laveran  and  Mesnil  found  that  when  Trypanosoma  gambiense  is  placed  in 
horse  serum  or  salt  solution  it  remains  alive  for  from  five  to  six  days  and  for 
some  time  longer  in  blood  agar.  Tubes  of  rabbit's  blood  agar  inoculated 
with  blood  containing  this  organism  showed  living  trypanosomes  for  28  days 
after  inoculation  when  kept  at  a  temperature  of  220  C.  They  also  observed 
that  division  occurred  upon  such  culture  media  and  that  the  trypanosomes 
were  much  larger  than  those  observed  in  the  blood  of  man.  They  were  not 
able  to  secure  subcultures. 

Biological  Phenomena. — Trypanosoma  gambiense,  like  all  other  organisms 
of  this  class,  shows  no  nutritive  vacuoles,  and  therefore  must  nourish  itself  by 
a  process  of  osmosis.  They  do  not  feed  upon  the  red  blood-corpuscles  nor 
enter  them,  but  haemoglobin  appears  to  be  essential  to  their  growth  upon 
culture  media,  as  proven  by  Novy  and  MacNeal's  experiments. 

They   possess   active    motility,    which    varies   in   rapidity   under   certain 


THE    BLOOD    PROTOZOA    OF    MAN.  437 

conditions.  Cold  evidently  decreases  motility  very  decidedly,  and  exposure 
of  the  blood  containing  them  to  the  air  also  lessens  activity.  The  motility  is 
chiefly  due  to  the  undulating  membrane  and  the  flagellum,  but  the  protoplasm 
possesses  contractility,  which  causes  marked  contraction  of  the  body  as  well 
as  a  form  of  amoeboid  motion.  The  organism  progresses  either  with  the 
flagellum  forward  or  backward,  but  generally  with  the  flagellum  forward. 
The  flagellum  possesses  a  lashing  movement  which  is  easily  made  out  in  the 
more  sluggish  organisms,  while  the  movement  of  the  undulating  membrane 
consists  in  undulations  in  various  directions.  In  the  blood  of  man  the  trypano- 
some  often  moves  so  rapidly  that  it  is  impossible  to  detect  either  the  movement 
of  the  flagellum  or  the  undulating  membrane. 

Pathogenicity  of  Trypanosoma  gambiense. — This  trypanosome  is 
pathogenic  for  a  large  number  of  animals  besides  man.  Its  pathogenicity 
varies  considerably,  due,  as  in  all  pathogenic  trypanosomes,  to  conditions  which 
have  not  yet  been  thoroughly  demonstrated.  Its  virulence  depends  upon  the 
race  and  species  of  animals  inoculated,  upon  the  orgin  of  the  trypanosoma 
inoculated,  and  upon  successive  passage  through  certain  species  of  animals. 

In  monkeys,  of  which  the  Macacus  and  Cercopithecus  are  most  susceptible, 
the  inoculation  of  blood  containing  Trypanosoma  gambiense  is  followed  some- 
times by  slight  fever  and  the  symptoms  of  a  typical  attack  of  sleeping  sickness, 
but  more  often  the  only  symptoms  noted  are  emaciation,  anaemia,  lowering  of 
the  temperature,  and  a  tendency  to  slumber.  The  trypanosomes  may  be 
demonstrated  in  the  blood  and  in  the  cerebrospinal  fluid  in  those  cases  which 
present  marked  cerebral  symptoms.  It  is  very  probable  that  infection  with 
this  trypanosome  in  the  monkey  is  always  fatal.  The  higher  apes  appear  to 
be  more  resistant  to  infection  than  the  lower,  but  typical  trypanosomiasis 
has  been  produced  in  baboons  by  Thomas  and  Linton,  Gray  and  Tulloch,  and 
Thomas  and  Breinl.  Bruce,  Nabarro,  and  Greig  have  observed  typical  lethargy 
in  the  monkey  weeks  before  death  occurred.  The  period  of  incubation  in 
monkeys  varies  from  9  to  40  days,  the  average  being  18  days.  The  duration 
of  the  disease  was  usually  seven  months,  but  the  animals  may  live  over  a  year 
after  infection. 

In  dogs  this  organism,  when  inoculated,  produces  a  chronic  infection 
varying  in  duration  from  two  to  nine  months,  as  a  rule.  The  period  of  incuba- 
tion and  the  duration  of  the  disease  in  the  dog  is  very  variously  given  by  dif- 
ferent investigators,  thus  proving  that  they  worked  with  trypanosomes  varying 
greatly  in  virulence.  The  Uganda  Commission  found  the  incubation  period 
to  be  from  two  to  five  weeks  in  dogs,  while  Brump  and  Wurtz  give  the  incuba- 
tion period  as  17  days;  these  authors  state  that  the  duration  of  the  disease  is 
36  days,  while  Thomas  and  Linton  give  the  duration  as  from  three  weeks  to 
nine  months. 

The  symptoms  are  emaciation,  anaemia,  and  a  subnormal  temperature 
before  death,  although  during  the  infection  the  temperature  may  be  higher 
than  normal  at  intervals.     The  trypanosomes  may  be  found  in  the  blood  in 


438  THE    BLOOD   PROTOZOA   OF   MAN. 

small  numbers.  Gray  and  Tulloch  found  that  around  Lake  Albert  the  dogs 
were  naturally  infected  with  Trypanosoma  gambiense. 

This  trypanosome  is  also  infective  to  the  jackal  (Nabarro),  cats,  rabbits, 
guinea-pigs,  white  rats,  mice,  jerboas  (Laveran),  marmots,  goats,  sheep,  and 
horses.  Cattle  are  very  resistant,  but  may  be  infected.  In  all  of  these  animals 
the  infection  runs  a  chronic  course,  and  does  not  result  fatally  in  the  larger 
mammals,  as  the  sheep,  horses,  and  cattle.  In  goats  the  infection  may  be  a  very 
fatal  one,  as  shown  by  the  experiments  of  Thomas  and  Breinl. 

Methods  of  Transmission. — It  has  been  determined  that  Trypanosoma 
gambiense  is  transmitted  to  man  through  the  agency  of  biting  flies  belonging 
to  the  genus  Glassina.  To  Bruce  and  Nabarro  we  owe  the  first  demonstra- 
tion that  Glossina  palpalis  is  the  chief  agent  in  the  transmission  of  the  trypano- 
some of  sleeping  sickness,  for  in  August,  1903,  these  investigators  reported  a 
successful  infection  of  a  Cercopithccus  monkey  by  the  bites  of  numerous  flies 
of  this  genus.  A  later  report  gives  the  results  these  authors  obtained,  in 
conjunction  with  Greig  (1903,  November),  in  the  experimental  infection  of 
monkeys  by  the  bites  of  infected  Glosinna  palpalis.  These  flies  were  allowed 
to  suck  the  blood  of  infected  negroes  and  were  then  placed  upon  the  monkeys, 
and  after  an  incubation  period  of  about  two  months  the  trypanosomes  were 
demonstrated  in  the  blood  of  the  animals.  They  also  proved  that  the  flies  were 
able  to  infect  monkeys  24  to  48  hours  after  biting  the  infected  negro,  but,  as 
has  been  stated,  no  developmental  stages  of  the  trypanosomes,  indicating  a 
sexual  cycle,  have  been  found  in  the  stomachs  of  the  flies.  The  discovery  of 
the  etiological  relationship  of  this  fly  to  sleeping  sickness  at  once  explained  the 
occurrence  of  the  disease  only  in  certain  localities,  for  further  investigation  has 
shown  that  sleeping  sickness  is  found  only  where  flies  belonging  to  the  genus 
Glossina  abound. 

The  discovery  by  Wellman,  of  a  new  species  of  Glossina,  Gl.  palpalis  well- 
mani  Austen,  in  South  Angola,  and  by  Massey,  in  the  Upper  Congo,  where 
sleeping  sickness  occurs,  indicates  that  this  fly,  as  well  as  palpalis,  is  capable  of 
transmitting  the  trypanosome,  and  Nabarro  and  Greig  have  apparently  proven 
that  Gl.  pallidipes,  Gl.fusca,  and  Gl.  longipennis  are  able  to  convey  Trypanosoma 
gambiense  from  sick  to  healthy  animals. 

So  far  as  we  know,  the  infection  is  carried  from  the  sick  to  the  well  by  the 
proboscis  of  the  fly,  as  no  evidence  exists  that  the  trypanosomes  undergo  any 
development  within  the  insect,  and  the  fly  is  not  infective  after  48  hours.  As 
so  many  of  the  lower  animals  are  susceptible  to  infection  with  this  trypanosome, 
which  produces  in  most  of  them  a  chronic  disease  in  which  the  organisms  are 
present  in  the  blood  for  weeks  or  months,  it  is  easy  to  understand  how  the 
disease  is  maintained  in  localities  where  it  is  endemic,  and  how  difficult  it 
has  proven  to  rid  a  locality  of  the  infection. 

Distribution  in  Man. — In  man  Trypanosoma  gambiense  is  found  in  the 
blood,  in  the  lymphatic  glands,  the  cerebrospinal  fluid,  and  in  the  various 
organs,  within  the  capillaries.     The  organism  occurs  in  small  numbers  in  the 


THE    BLOOD    PROTOZOA    OF    MAN.  439 

blood,  in  larger  numbers  within  the  lymph  glands,  and  in  large  numbers  in  the 
cerebrospinal  fluid  in  well-marked  cases  of  sleeping  sickness,  after  the  develop- 
ment of  cerebral  and  spinal  symptoms.  In  sections  of  the  organs  of  patients 
dying  from  this  disease  the  trypanosomes  are  seldom  found,  but  they  have  been 
demonstrated  in  the  spleen,  the  liver,  the  bone-marrow,  and  the  lungs. 
The  pathological  changes  produced  by  infection  with  this  parasite  comprise 
hypertrophy  of  the  lymphatic  glands,  lesions  in  the  meninges  resembling  those 
of  cerebrospinal  meningitis,  chronic  inflammatory  lesions  of  the  lymphatics  of 
the  central  nervous  system,  and  degeneration  of  the  spinal  cord.  The  pathogno- 
monic lesion,  according  to  Mott,  to  whom  we  owe  our  most  exact  knowledge  of 
the  pathology  of  sleeping  sickness,  consists  in  "the  universal  perivascular  cell- 
infiltration  of  the  central  nervous  system."  He  also  states  that  the  changes 
observed  in  the  nervous  system  are  almost  identical  with  those  observed  in 
syphilis  with  the  exception  that  in  this  disease  the  proliferative  endarteritis 
leading  to  thrombosis  is  absent,  whereas  it  is  common  in  syphilis. 

Demonstration  of  Trypanosoma  Gambiense. — The  diagnosis  of  sleep- 
ing sickness  can  be  made  by  an  examination  of  the  blood,  the  cerebrospinal 
fluid,  and  juice  from  the  enlarged  lymphatic  glands.  In  all  of  these  fluids  the 
trypanosomes  occur,  but  they  are  said  to  be  most  easily  demonstrated  in  the 
juice  obtained  from  the  enlarged  lymphatic  glands  of  the  cervical  region.  For 
staining  the  modification  of  Wright's  method  which  I  use  in  staining  malarial 
blood  is  most  useful,  but  any  of  the  modifications  of  the  Romanowsky  stain, 
such  as  Leishman's,  Jenner's,  or  the  Giemsa  stain,  may  be  used. 

Examination  of  the  Blood. — The  blood  may  be  examined  either  fresh  or 
stained.  As  the  trypanosomes  occur  but  in  small  numbers  in  the  blood  it 
is  better  to  make  several  smears  for  staining,  as  in  this  way  more  time  can  be 
given  to  the  examination,  and  a  greater  number  of  specimens  examined  at 
leisure.  It  is  generally  better  to  use  some  method  of  centrifuging  the  blood  as 
the  parasites  are  so  few  in  number  that  many  smears  prepared  in  the  ordinary 
way  will  have  to  be  examined  before  a  trypanosome  is  encountered. 

The  method  of  examination  recommended  by  Bruce  and  Nabarro  is  an 
excellent  one  and  is  as  follows:  About  10  c.c.  of  blood  is  removed  from  a  vein 
and  placed  in  a  centrifuge  tube  containing  a  small  amount  of  sodium  citrate 
solution  and  centrifuged  for  10  minutes.  The  supernatant  serum,  the  leucocyte 
layer,  and  the  upper  portion  of  the  red  layer  is  pipetted  off  and  again  centrifuged 
for  ten  minutes,  after  which  the  upper  layer  is  pipetted  off  and  centrifuged  for 
the  same  time.  A  small  drop  of  the  supernatant  liquid  so  obtained  is  placed 
upon  a  slide  and  examined  as  a  fresh  preparation,  and  if  the  trypanosomes  are 
not  present  in  this  a  portion  of  the  sediment  should  be  examined,  in  which  they 
will  surely  be  found  if  the  case  is  one  of  sleeping  sickness.  An  examination 
should  be  made  of  each  specimen  before  it  is  recentrifuged  as  the  trypanosomes 
may  be  found  after  once  centrifuging  only.  Smears  may  be  prepared  from  the 
sediment  and  stained. 

Examination  of  the  Cerebrospinal  Fluid. — In  order   to   obtain    the 


44°  THE    BLOOD    PROTOZOA    OF    MAN. 

cerebrospinal  fluid  for  examination  it  is  necessary  to  perform  lumbar  puncture. 
The  following  method  of  performing  this  operation  is  that  recommended  by 
Tuffier  (L'Analgesie  chirurgicale  par  voie  rachidienne,  Paris,  1901)  as  given  in 
Laveran  and  Mesnil's  classical  work  upon  "Trypanosomes  and  Trypano- 
somiases," translated  by  Nabarro. 

"Use  a  platinum-iridium  needle  (which  can  be  sterilized  easily)  8  centi- 
meters (about  31/2  inches)  long,  fitted  to'a  hypodermic  syringe.  The  external 
diameter  of  the  needle  should  be  1  millimeter,  and  the  internal  diameter  o.O 
millimeter;  the  point  should  be  bevelled  off  very  little.  It  is  unnecessary  to  use 
a  general  anaesthetic.  The  patient  should  sit  up  with  the  arms  held  in  front. 
The  lumbar  region  is  thoroughly  washed  and  rendered  aseptic.  The  iliac  crests 
are  used  as  a  guide,  the  transverse  line  joining  their  highest  points  crossing  the 
spine  at   the  level  of  the  fourth  lumbar  vertebra  (spinous  process). 

"  The  left  index  finger  being  placed  on  this  spinous  process,  the  patient  is  told  to 
bend  the  head  well  forward.  This  serves  to  separate  the  laminae  of  the  vertebrae 
between  which  the  needle  has  to  pass.  At  the  moment  of  inserting  the  needle 
the  patient  must  be  warned  that  he  is  going  to  be  pricked,  and  that  he  must 
remain  perfectly  still  and  on  no  account  straighten  the  back  by  sitting  uprigh.1  . 
The  needle  of  the  syringe,  properly  sterilized,  is  introduced  at  a  point  1  centi-. 
meter  (about  1  /  2  an  inch)  from  the  middle  line  close  up  against  the  edge  of  the 
index  finger,  which  is  kept  on  the  spinous  process.  The  point  of  the  needle  is 
directed  slightly  toward  the  middle  line  and  upward,  and  when  it  enters  the 
subdural  space  it  is  distinctly  felt  that  there  is  no  longer  any  resistance.  A 
clear  liquid  immediately  wells  up  into  the  needle  and  can  be  collected  in  a  tube, 
or  a  syringe  can  be  fitted  to  the  needle." 

Nabarro  recommends  slight  aspiration  if  the  needle  becomes  clogged  and 
states  than  in  sleeping  sickness  the  cerebrospinal  fluid,  on  account  of  the 
increased  pressure  in  the  spinal  canal,  often  spurts  out  of  the  needle  in  a  steady 
stream  and  as  much  as  50  c.c.  may  be  collected  at  one  time.  The  administra- 
tion of  a  general  anaesthetic  should,  in  most  cases,  be  insisted  upon,  as  the 
operation  is  much  easier  when  the  anaesthetic  is  given,  and  both  Nabarro  and 
Christy  recommend  chloroform. 

In  the  cerebrospinal  fluid  the  trypanosomes  are  generally  few  in  number 
and  it  is  necessary  to  centrifuge  the  fluid  for  ten  minutes  and  the  sediment 
should  be  examined  fresh  or  stained  preparations  made,  using  one  of  the 
chromatin  stains.  Nabarro  states  that  in  a  few  instances  the  trypanosomes 
were  so  numerous  that  they  were  detected  in  the  fluid  before  it  was  centrifuged, 
but  he  also  states  that  in  other  cases  it  was  necessary  to  perform  lumbar  puncture 
as  many  as  four  times  before  the  parasite  was  discovered.  It  is  probable  that  the 
trypanosome  is  always  present  in  the  cerebrospinal  fluid  in  every  case  of  sleep- 
ing sickness,  but  repeated  examinations  may  have  to  be  made  in  order  to  demon- 
strate it.  A  certain  periodicity  appears  to  be  present  as  regards  the  occurrence 
of  the  trypanosomes  in  the  cerebrospinal  fluid,  and  they  are  never  found  there 
in  the  earlier  stages  of  trypanosomiasis,  only  appearing  when  the  symptoms 
characteristic  of  sleeping  sickness  appear. 

In  stained  smears  made  from  the  cerebrospinal  fluid  the  trypanosomes  do 


THE    BLOOD    PROTOZOA    OF    MAN.  44 1 

not  appear  well  stained,  and  for  this  reason  it  is  not  advisable  to  stain  such 
organisms,  but  to  examine  them  in  the  fresh  fluid. 

Examination  of  the  Gland  Juice. — The  discovery  by  Greig  and  Gray 
that  the  juice  of  the  lymphatic  glands  in  human  trypanosomiasis  contained  the 
trypanosomes  in  comparatively  large  numbers  has  proven  of  the  greatest 
service  in  diagnosis.  These  investigators,  following  a  suggestion  made  by 
Mott,  examined  the  contents  of  the  lymphatic  glands  in  15  cases  of  sleeping 
sickness  and  found  the  trypanosomes  in  all  of  them,  and  that  the  organisms 
were  much  more  numerous  than  in  either  the  blood  or  the  cerebrospinal  fluid. 
They  also  found  the  organisms  in  the  lymphatic  glands  of  patients  suffering 
from  trypanosomiasis  in  whom  the  symptoms  of  sleeping  sickness  had  not 
appeared.  At  first  they  excised  the  glands,  but  later  found  that  this  was  not 
necessary,  one  of  the  enlarged  glands  being  punctured  with  the  needle  of  a 
hypodermic  syringe  and  some  of  the  juice  of  the  gland  aspirated  into  the 
syringe,  placed  upon  microscopic  slides  and  examined  at  once  or  stained.  The 
cervical  glands  were  fcund  to  cor. tain  the  orgarisms  in  greatest  numbers,  but 
they  were  also  demonstrated  in  the  enlarged  femcral  and  inguinal  glands. 

Nabarro  gives  the  following  directions  regarding  the  technic  of  gland 
puncture: 

"Gland  puncture  is  quite  a  simple  operation,  but  it  is  necessary  to  attend 
to  a  few  details  of  technic.  The  syringe  must  be  boiled  before  use,  then  washed 
with  a 'sterile  salt  solution,  every  trace  of  which  should  be  got  rid  of  before  using 
the  syringe.  After  obtaining  the  drop  of  gland  juice,  the  piston  should  be 
allowed  to  return  almost  as  far  as  it  will,  and  then  fixed  with  the  finger,  other- 
wise much  of  the  fluid  aspirated  would  be  lost  in  the  body  of  the  syringe.  The 
drop  of  fluid  in  the  syringe  must  be  pushed  out  by  one  sharp  push  of  the  piston 
rather  than  by  two  or  three  movements,  so  as  to  avoid  getting  air  bubbles  in  the 
preparation.  The  drop  is  quickly  covered  with  a  cover-glass  (care  being  taken 
to  avoid  the  minute  piece  of  skin  punched  out  by  the  needle)  ringed  with  vase- 
line, and  examined  at  once  (Todd)." 

The  observations  of  Greig  and  Gray  have  been  confirmed  by  Dutton  and 
Todd,  as  well  as  many  other  investigators,  and  it  is  generally  acknowledged 
to-day  that  gland  puncture  is  the  best  method  of  demonstrating  Trypanosoma 
gambiense  in  early  cases  of  trypanosomiasis  and  also  in  those  cases  in  which 
the  symptoms  of  sleeping  sickness  have  already  developed.  It  is  especially  in 
the  early  cases  of  infection  that  this  method  is  valuable,  as  in  such  patients  the 
trypanosomes  are  very  scanty  in  the  blood  and  absent  from  the  cerebrospinal 
fluid,  but  are  often  numerous  in  the  gland  juice.  The  posterior  cervical  glands 
have  given  the  best  results,  according  to  Nabarro  (95  per  cent.),  the  axillary, 
the  femoral,  and  the  epitrochlear  following  in  order.  The  trypanosomes 
obtained  in  glandular  juice  stain  better  than  those  from  the  cerebrospinal 
fluid,  but  not  as  well,  in  most  instances,  as  those  obtained  from  the  blood.  The 
trypanosomes  have  also  been  found  in  pleural,  peritoneal,  and  pericardial 
exudates  and  in  hydrocele  fluid. 


442  THE    BLOOD    PROTOZOA    OF    MAN. 

Staining. — For  diagnostic  purposes  staining  is  not  necessary  if  gland 
juice  or  cerebrospinal  fluid  is  to  he  examined,  as  the  trypanosomes  are  easily 
recognized  by  their  active,  wriggling  movements  and  their  peculiar  spindle 
shape.  Examination  of  these  fluids  should  be  made  with  a  i ,  6  inch  objective 
and  several  specimens  should  be  examined  before  a  negative  result  is  recorded. 
The  cerebrospinal  fluid  should  be  centrifuged  if  an  examination  of  the  uncentri- 
fuged  fluid  is  negative.  In  staining  with  Wright's  or  Leishman's  stain  the  stain 
should  first  be  allowed  to  fix  the  preparation  of  blood  or  other  substance  for 
five  minutes,  the  water  then  added,  and  the  stain  allowed  to  act  for  from  ten 
to  twenty  minutes  longer,  the  time  being  judged  by  the  staining  reactions  as 
observed  after  experimentation  with  several  specimens.  In  well  stained  prepara- 
tions the  protoplasm  of  Trypanosoma  gambiense  should  be  colored  a  well- 
marked  blue,  the  nucleus  a  crimson  or  dark  red,  the  blepharoplast  a  darker 
red  or  brilliant  violet,  and  the  flagellum,  from  its  origin  at  the  blepharoplast, 
along  the  edge  of  the  undulating  membrane  and  throughout  its  free  portion 
a  dark  red  or  violet,  the  undulating  membrane  being  blue  in  color.  Good 
specimens  can  be  secured  only  after  a  certain  amount  of  experimentation,  and 
the  beginner  should  not  be  discouraged  if  the  first  few  specimens  stained  by 
him  do  not  show  perfectly  the  morphology  of  the  trypanosome. 

Other  Mammalian  Trypanosomes. — For  convenience  in  reference  the 
following  list  of  the  trypanosomes  of  most  interest  which  infect  mammals  is 
appended. 

Trypanosoma  lewisi.  Kent.  1879.  A  parasite  of  rats,  generally  non- 
pathogenic, but  sometimes  pathogenic.     Discovered  by  Chaussat  in  1850. 

Trypanosoma  evansi.  Steel.  1885.  A  parasite  of  horses,  mules, 
elephants,  camels,  carabao  (the  Philippines)  buffaloes  and  dogs.  Produces  in 
horses  and  mules  the  disease  known  as  "surra."     Discovered  by  Evans  in  1880. 

Trypanosoma  briicei.  Plimmer  and  Bradford.  1899.  A  parasite  of 
horses  and  most  of  the  game  animals  of  Africa.  Causes  the  disease  known  as 
"nagana"  in  horses.  Transmitted  by  the  Glossing.  Discovered  by  Bruce  in 
1895. 

Trypanosoma  equiperdum.  Doflein.  1901.  A  parasite  of  horses  and 
donkeys,  transmitted  by  coitus.  It  causes  in  these  animals  the  disease  known  as 
dourine,  or  "  malady  du  coit."     Discovered  by  Rouget  in  1894. 

Trypanosoma  equinum.  Voges.  1901.  A  parasite  of  horses,  causing  the 
disease  known  as  "mal  de  caderas."     Discovered  by  Elmassian,  in  1901. 

Trypanosoma  theileri.  Laveran.  Bruce.  1902.  A  parasite  of  cattle. 
Produces  in  these  animals  the  disease  known  as  galziekte  (gall  sickness). 
Discovered  by  Theiler  in  the  Transvaal. 

Trypanosoma  dimorphon.  Dutton  and  Todd.  1904.  A  parasite  of 
the  horse  and  probably  of  sheep,  cattle,  antelopes,  dogs,  and  pigs.  Causes  in 
horses  the  disease  known  as  Gambian  horse  disease.  Discovered  by  Dutton 
and  Todd  in  1902. 


THE    BLOOD    PROTOZOA    OF    MAN.  443 

Literature  upon  Human  Trypanosomiasis. 

1803.      Winterbottom.     An  Account  of  Native  Africans  in  the  Neighborhood 

of  Sierra  Leone.      London. 
1899.     Mott,  W.  F.     The  Changes  in  the  Central  Nervous  System  of  Two  Cases 

of  Negro  Lethargy.      Brit.  Med.  Jour.,  December  16. 
1902.      Dutton,  J.  E.      Preliminary  Note  upon  a  Trypanosome  Occurring  in  the 

Blood  of  Man.      Thomp. -Yates.  Lab.  Rep.,  vol.  iv,  p.  453. 
1902.      Warrington,  W.  B.     A  Note  on  the  Condition  of  the  Central  Nervous 

System  in  a  Case  of  African  Lethargy.     Brit.  Med.  Jour.,  Sept.  27,  p.  929. 

1902.  Forde,    R.   M.      Some  Clinical   Notes  on  a  European  Patient  in  whose 
Blood  a  Trypanosoma  was  Observed.     Jour.  Trop.  Med.,  Sept.  1,  261. 

1903.  Castellani,  A.  Presence  of  Trypanosoma  in  Sleeping  Sickness.  Rep. 
Sleeping  Sickness  Commis.,  Roy.  Soc,  No.  1,  p.  3. 

1903.      Idem.      Researches  in  the  Etiology  of  Sleeping  Sickness.     Jour,  of  Tropical 

Medicine,  June  1,  p.  167. 
1903.      Idem.      Adult   Forms   and    Developmental   Forms  of   the  Trypanosome 

Found    in    Sleeping    Sickness.      Rep.    Sleeping    Sickness    Commis.,   Roy. 

Soc,  No.  2,  p.  9. 
1903.      Idem.      Some    Observations    on    the    Morphology  of    the   Trypanosoma 

Found  in  Sleeping  Sickness.      Brit.  Med.  Jour.,  vol.  ii,  No.  20,  p.  2216. 
1903.      Bruce  and   Nabarro.      Reports  of  the  Sleeping  Sickness  Commission, 

Royal  Society,  No.  1,  p.  11. 
1903.      Idem.     Further  Report  on  Sleeping  Sickness  in  Uganda.     Ibid.,  No.  4. 
1903.      Christy,   C.      The   Epidemiology  and  Etiology  of  Sleeping  Sickness  in 

Equatorial  Africa.      Rep.  Ibid.,  No.  3. 
1903.      Boyce,    Ross,   and   Sherrington.     The   History  of    the    Discovery  of 

Trypanosomiasis  in  Man.      Lancet,  vol.  ii,  p.  21. 
1903.      Manson,    Sir   P.      Trypanosomiasis    on    the   Congo.   Jour.    Trop.    Med., 

March  16,  p.  85. 
1903.      Rabinowitsch  and  Kempner.      Die  Trypanosomen  in  der  Menschen-  und 

Tierpathologie,  etc.     Centralbl.  f.  Bakt.  Orig.,   Bd.  xxxiv,   No.  8,  p.  804; 

Jour.  Trop.  Med.,  Dec.  15,  p.  389. 
1903.      Sambon.      Sleeping  Sickness  in    the  Light  of  Recent  Knowledge.     Jour. 

Trop.  Med.,  July  1,  p.  201,  vol.  vi,  No.  13. 
1903.      Dutton   and   Todd.      Researches  on  Trypanosomiasis  in   West  Africa. 

Brit.  Med.  Jour.,  vol.  ii,  Sept.  19,  p.  650. 

1903.  Novy  and  McNeal.  The  Cultivation  of  Trypanosoma  Brucei.  Jour, 
of  Am.  Med.  Assoc,  Nov.  21,  p.  1266. 

1904.  Blanchard,   R.      Arch,  de  Parisitologie,  vol.  ix,  No.  4,  p.  573. 

1904.  Dutton,  Todd,  and  Christy.  Reports  of  the  Trypanosomiasis  Expe- 
dition to  the  Congo.  1 903-1 904.  Liverpool  School  of  Tropical  Med., 
Mem.  xii. 

1904.  Chatterjee,  G.  C.  Notes  on  a  Few  Cases  of  Trypanosomiasis  in  Man. 
Lancet,  vol.  xii,  No.  3. 

1904.  Christy,  C.  Sleeping  Sickness  (Trypanosomiasis).  Brit.  Med.  Jour., 
vol.  ii,  p.  26. 

1904.  Greig  and  Gray.  Note  on  the  Lymphatic  Glands  in  Sleeping  Sickness. 
Lancet,  4,  vi. 

1904.  Low  and  Mott.  Examination  of  Tissues  in  Case  of  Sleeping  Sickness 
in  a  European.      Brit.  Med.  Jour.,  30,  iv. 

1904.  Sambon,  L.  W.  The  Elucidation  of  Sleeping  Sickness.  Jour.  Trop. 
Med.,  vol.  vii,  No.  4,  p.  61. 


444  TIIE    BLOOD    PROTOZOA    OF    MAX. 

igo4.      SAMBON,   L.    W.      The  Transmission  of  Sleeping  Sickness  by  Flies  of  the 

genus  Glossina.      Brit.  Med.  Jour.,  vol.  i.  No.  2255,  p.  696. 
1004.      Thomas  and  Linton.      Lancet,  May  14,  p.   1337. 

1004.  Nabarro.      Epidemiological  Society.      Lancet,  Jan.  23. 
1U04.      Laveran,  C.  R.      Acad.  Sciences,  Apr.  5. 

1Q04.      Brumpt  and  Wtjrtz.      Soc.  de  Biol.,  March  26,  p.  567. 

[904.      Christy,    C.      One    Hundred   and    Four  Lumbar  Punctures.     Thompson- 

Yates  and  Johnson  Lab.  Reports,  vol.  vi,  p.  57. 
11105.      Gray  and  Tullocii.      The  Multiplication  of  T.  gambiense  in  the  Alimen- 
tary Canal   of  Glossina  Palpalis.      Rep.  Sleeping  Sickness  Commis.  Roy. 

Soc,  No.  6,  p.  2S2. 
[905.      Greig  and  Gray.      Continuation  Report  on  Sleeping  Sickness  in  Uganda. 

Rep.  Sleeping  Sickness  Commis.  Roy.  Soc,  No.  6,  p.   1. 
[905.      Plimmer.      Proc.  Roy.  Soc,  vol.  v,  No.  74,  p.  388. 
190$.      Thomas   and    Breinl.     Thompson- Yates    and    Johnson,   Lab.   Reports, 

vol.  vi,  part  ii,  p.  93. 
[905.      Mott,  F.  W.      Observations  on  the  Brains  of  Men  and  Animals  infected 

with    Various   Forms   of   Trypanosomes.      Proc.    Roy.    Soc,  Ser.   B,  vol. 

lxxvi,   p.  235. 

1905.  Breinl,  A.      Thompson-Yates  Lab.  Reports,  vol.  vi,  part  ii,  p.  66. 

1005.  Dutton  and  Todd.  Thompson-Yates  and  Johnson  Lab.  Reports,  vol. 
vi,  part  ii,  p.  97. 

1906.  Laveran,  C.  R.      Acad.  Sciences,  vol.  cxlii,  p.   10O5. 

1906.     Wellman.      Trypanosomiasis  in  Angola.      Jour.   Hygiene,  vol.  v,   No.  6, 

p.  237.      ("  Notes  from  Angola.  ") 
1906.      Mott,  F.    W.      Pathology  of  Trypanosomiasis.      Rep.   Sleeping  Sickness 

Commis.  Roy.  Soc,  No.  7. 

1906.  Mole.  The  Lesions  in  the  Lymphatic  Glands  in  Human  Trypanosomi- 
asis. Liverpool  School  Tropical  Med.  Memoirs,  21,  p.  69. 

1907.  Gray  and  Tulloch.      Rep.   Sleeping  Sickness  Commis.   Roy.  Soc,  No. 

8,  P-  133- 

1007.      Minchin,    Gray,  and    Tulloch.      Glossina   Palpalis   in    its    Relation   to 

Trypanosoma   gambiense    and  other  Trypanosomes.      Jour.   Roy.  Army 

Med.  Corps,  p.  568. 
1907.      Manson,  Sir  P.      Tropical  Diseases.      London,  p.  150. 
1907.      Bruce,     D.      Trypanosomiasis.      Osier's     "Modern    Medicine,"      vol.    i, 

p.  460,  Philadelphia. 
1907.      Stephens,  J.  W.  W.  Trypanosomiasis.      System  of  Medicine  by  Allbutt 

and  Rolleston,  vol.  ii,  part  ii,  p.  207,  London. 

1906.  Now,  F.  G.  The  Trypanosomes  of  Tsetse  Flies.  Jour.  Infec.  Dis., 
vol.  iii,  No.  3,  p.  394. 

1907.  Idem.      Trypanosomes.      Jour.  Am.  Med..  Assoc,  vol.    xlviii,   Jan.    5-12. 

1907.  Laveran  .Mesnil,  and  Nabarro.  Trypanosomes  and  Trypanosomiasis. 
London  and  Chicago. 

1908.  Stephens  and  Christophers.  Practical  Study  of  Malaria  and  Other 
Blood  Parasites,  p.  313,  London. 

1908.      Rogers,  Leonard.     Fevers  in  the  Tropics,  London,  p.  90. 

1908.  Ward,  H.  B.  "Protozoa"  in  Ref.  Handbook  Med.  Sciences.  Revised 
Appendix,  p.  643,  New  York. 

1908.  Martin  and  Leboeuf.  The  Microscopical  Diagnosis  of  Human  Trypano- 
somiasis.     Bull.  Soc.  Path,  exot.,  t.  i,  p.  126. 

1908.      Idem.      Glandular  Enlargement  in  Sleeping  Sickness,  Ibid.,  p.  221. 


CHAPTER  III. 

The   Spirochaetes;1    Spirochaeta   Recurrentis;   Spirochaeta   Duttoni;  Spirochaeta 
Carteri;  Spirochaeta  Novyi   (Spiroschaudinnia). 

The  spirochaetae  are  parasites  of  the  blood  causing  a  group  of  relapsing 
fevers  endemic  in  certain  localities.  It  was  supposed  for  a  long  time  that  only 
one  spirochaeta,  Spirochaeta  recurrentis  {Spirillum  obermeieri)  caused  relapsing 
fever,  but  the  recent  investigations  of  Novy  and  Knapp,  Breinl  and  Todd, 
Dutton,  Prowazek,  Carter,  and  others  have  definitely  proven  that  there  are  at 
least  four  species,  each  causing  a  peculiar  form  of  relapsing  fever,  and  each 
apparently  limited  in  geographical  distribution. 

Historical. — Relapsing  fever  has  been  known  since  the  time  of  Hippocrates 
but  nothing  was  known  of  its  etiological  factor  until  Obermeier,  in  1873, 
described  an  organism  occurring  in  the  blood  of  patients  suffering  from  the 
disease,  to  which  Cohn  gave  the  name  Spirillum  obermeieri,  but  which  had  been 
previously  named  Spirochaeta  recurrentis  by  Lebert  in  1874.  Obermeier  and 
others  proved  that  this  organism  produced  the  symptoms  of  relapsing  fever  in 
animals,  and  observation  has  since  demonstrated  that  the  organism  is  invariably 
present  in  the  blood  of  cases  of  relapsing  fever  occurring  in  certain  parts  of 
Europe,  notably  Russia  and  the  Balkans.  The  occurrence  of  relapsing  fever 
in  India,  Africa,  and  in  America,  associated  with  similar  organisms,  led  to 
the  belief  that  all  cases  of  relapsing  fever  were  due  to  this  spirochaeta,  but 
Manson,  Sambon,  and  Koch,  in  1904  and  1905,  suggested  that  on  account 
of  geographical  distribution,  and  clinical  differences,  there  might  be  a  group  of 
relapsing  fevers  due  to  specific  organisms,  and  to  Novy  and  Knapp  we  owe 
the  first  definite  demonstration  that  distinct  morphological  differences  existed 
between  the  spirochaetae.  In  a  paper  published  in  1906  these  authors,  as  the 
result  of  their  study  of  spirochaetae  from  Europe  and  Africa,  concluded  that 
the  spirochaeta  of  relapsing  or  tick  fever  of  Africa  is  a  distinct  species,  and 
named  it  Spirillum  duttoni,  while  they  also  state  that  the  organism  found  in  the 
blood  of  relapsing  fever  in  India  is  probably  a  distinct  species.  As  will  be  seen 
later,  Novy  and  Knapp  regarded  all  spirochaetae  occurring  in  relapsing  fever 
in  man  as  bacteria,  belonging  to  the  spirilli.  The  observations  regarding  the 
African  spirochaeta  were  soon  confirmed  and  it  is  now  generally  admitted  that 
it  is  a  distinct  species.     The  investigations  of  Norris,  Flournoy,  Pappenheimer, 

1  I  have  included  these  organisms  among  the  blood  protozoa  provisionally, 
as  their  exact  biological  position  has  not  yet  been  definitely  settled  and  because 
they  are  blood  parasites.  Until  it  is  proven  that  they  are  bacterial  in  nature 
I  believe  that  they  should  be  regarded  as  belonging  to  the  Protozoa. 

445 


446  THE    BLOOD   PROTOZOA   OF   MAN. 

and  Novy  and  Knapp  upon  a  spirochaeta  found  in  the  blood  of  relapsing  fever 
cases  occurring  in  the  United  States  resulted  in  showing  that  this  organism  was 
probably  a  distinct  species,  and  Uhlenhuth  and  Haendel  proved  by  means  of 
agglutination  reactions  that  the  American  spirochaeta  is  different  from  others, 
and  this  organism  is  now  known  as  Spirochaeta  novyi.  Further  investigations 
of  the  spirochaeta  of  Indian  relapsing  fever  confirmed  the  belief  of  Novy  and 
Knapp  that  this  also  was  a  distinct  species,  and  to  it  Mackie  has  given  the 
name  "Spirochaeta  carteri."  As  the  result  of  these  various  studies  of  the 
spirochaetae  occurring  in  relapsing  fever,  we  recognize  at  the  present  time  the 
four  following  species: 

Spirochaeta  rccurroitis.  Lebert.  1874.  Causing  European  relapsing 
fever. 

Spirochaeta  duttoni.  Now  and  Knapp.  1906.  Causing  African  relapsing 
fever. 

Spirochaeta  novyi.    Schellach.    1907.    Causing  American  relapsing  fever. 

Spirochaeta  carteri.     Mackie.     190S.     Causing  Indian  relapsing  fever. 

Geographical  Distribution. — The  geographical  distribution  of  the  spiro- 
chaetae is  apparently  limited  as  regards  the  different  species,  each  species  being 
peculiar  to  the  country  in  which  it  is  found.  The  relapsing  fever  of  Africa, 
better  known  as  "tick  fever"  is  caused  by  Spirochaeta  duttoni,  and  the  geo- 
graphical distribution  of  this  organism  is  confined  to  the  continent  of  Africa; 
the  same  is  true  of  the  other  species,  Spirochaeta  recurrentis  being  peculiar  to 
Europe,  Spirochaeta  novyi  to  America,  and  Spirochaeta  carteri  to  Asia. 

Biological  Position. — The  biological  position  of  these  organisms  has 
not  been  definitely  determined,  scientists  being  divided  into  two  schools  regard- 
ing this  question,  one  believing  that  they  are  protozoa,  the  other  that  they  are 
bacteria.  It  is  actually  impossible  to  state  at  the  present  writing  which  school 
has  the  better  of  the  argument,  but  the  occurrence  of  longitudinal  division, 
which  I  believe  has  been  demonstrated  beyond  question  in  these  parasites, 
would  appear  to  prove  their  protozoal  nature.  It  must  be  admitted,  however, 
that  the  evidence  regarding  their  bacterial  nature  is  very  strong  and  that  further 
research  may  demonstrate  that,  in  reality,  they  possess  features  common  to 
both  the  protozoa  and  the  bacteria,  forming,  as  it  were,  a  connecting  link 
between  animal  and  vegetable  organisms. 

For  those  who  believe  in  the  bacterial  nature  of  these  organisms  they 
must  be  regarded  as  spirilli,  while  for  those  who  believe  in  their 'protozoan 
origin  they  are  placed  in  the  genus  "Spirochaetae."  Recently  some  zoologists, 
as  Sambon  and  Ward,  have  created  a  new  genus  to  include  the  parasites  of  the 
relapsing  fevers,  the  Spiroschaudinniae,  but  this  classification  has  not  been 
generally  adopted. 

Until  the  publication  of  Schaudinn's  paper  upon  Spirochaeta  ziemanni, 
the  cause  of  relapsing  fever,  commonly  known  as  Spirillum  obermeieri,  was 
regarded  as  a  bacterium,  but  his  statement  that  in  all  probability  all  spirochaetes 
would  be  found  to  be  developmental  stages  of  trypanosomes  (which  has  proven 


THE    BLOOD    PROTOZOA    OF    MAN.  447 

not  to  be  the  case)  and  the  demonstration  of  chromatin  and  an  undulating 
membrane  in  some  of  the  spirochaetae,  caused  investigators  to  study  anew  the 
organisms  concerned  in  the  etiology  of  relapsing  fever,  with  the  result  that  their 
bacterial  nature  was  disputed.  The  type  species  of  the  spirochaetae,  Spiro- 
chaeta  plicatilis,  possesses  a  distinct  undulating  membrane  and  is  devoid  of 
a  flagellum,  but  many  other  members  of  the  genus  differ  considerably  in 
morphology  from  this  typical  spirochaeta.  The  organisms  concerned  in  the 
etiology  of  relapsing  fevers  differ  so  markedly  from  a  typical  spirochaeta,  as 
described  by  Schaudinn,  that  I  believe  that  they  should  be  taken  from  that 
genus  and  placed  in  a  new  one,  that  already  adopted  by  Ward  (Spiro- 
schaudinnia)  being  available. 

Novy  and  Knapp,  who  are  ardent  advocates  of  the  bacterial  nature  of  the 
spirochaetes  of  relapsing  fevers,  believe  that  the  following  evidence  is  sufficient 
to  prove  that  they  belong  to  the  bacteria:  transverse  division;  multiple  flagella; 
absence  of  a  nucleus,  undulating  membrane  and  blepharoplast;  resistance  to 
plasmolytic  changes  and  to  heat;  and,  finally,  that  active  immunity  is  easily 
obtained,  which  is  not  true  of  protozoal  infections. 

The  evidence  that  these  organisms  are  protozoal  in  nature,  as  believed 
by  Schaudinn,  Prowazek,  and  other  zoologists,  consists  in  the  occurrence  of 
longitudinal  as  well  as  transverse  division;  the  presence  of  chromatin;  the  fact 
that  many  organisms  are  twice  as  thick  as  others,  these  being  the  forms  which 
undergo  longitudinal  division;  the  method  of  natural  transmission  by  an  insect, 
and  through  the  egg  of  an  insect;  the  reaction  of  the  organisms  to  solutions  of 
sodium  chloride  and  to  solutions  of  saponin  and  the  bile  salts,  and  the  demonstra- 
tion of  a  minute  mass  of  chromatin  projecting  from  some  portion  of  the  organism. 
It  is  evident  that  further  research  is  needed  before  a  definite  conclusion  can  be 
reached  regarding  the  exact  biological  position  of  these  parasites,  but  until  this 
is  possible  I  believe  that  it  is  wise  to  regard  them  as  belonging  to  the  Protozoa. 

Morphology  of  the  Spirochaetae  of  the  Relapsing  Fevers. — In 
describing  the  morphology  of  the  spirochaetae  causing  the  relapsing  fevers  of 
man  I  shall  describe  each  separately,  concluding  with  a  discussion  of  the 
differential  features  of  the  various  species. 

Spirochaeta  Recurrentis  (Spirillum  Obermeieri). — This  parasite  varies 
in  length  from  19//  to  29/i  and  in  breadth  from  0.3/z  to  0.5  //,  the  number  of 
curves  varying  from  four  to  eighteen,  the  organism  being  typically  spiral  in 
shape,  the  curves  marked  and  regular.  The  ends  are  pointed  and,  according 
to  Koch  and  Karlinsky,  one  or  more  flagella  are  present  at  each  end,  while 
Manson  states  that  the  flagellum  is  present  at  only  one  of  the  extremities. 
The  observation  of  Fraenkel  that  the  organism  possesses  numerous  peritrichous 
flagella  is  disputed  by  Prowazek  and  Schellach,  who  insist  that  the  flagella  seen 
by  Fraenkel  were  artefacts  produced  by  the  method  of  staining  employed. 
In  specimens  stained  by  any  modification  of  the  Romanowsky  stain  but  little 
structure  can  be  distinguished,  but  in  rare  instances  an  irregular  staining  is 
noticed,  the  body  of  the  parasite  containing  minute,  irregularly  distributed 


448  THE    BLOOD    PROTOZOA    OF    MAN. 

masses  of  substance  taking  the  chromatin  stain.  An  undulating  membrane  has 
been  described  by  Schaudinn  and  Leishman,  but  their  observations  concerning 
this  have  not  been  confirmed.  With  Giesma's  stain  the  organism  presents 
numerous  deeply  stained  granules  throughout  its  entire  length,  with  the  ex- 
ception of  the  ilagellum.  Both  transverse  and  longitudinal  division  occurs, 
transverse  division  being  the  most  frequent  method  of  reproduction,  but  the 
occurrence  of  Y-shaped  organisms,  which  can  only  be  regarded  as  forms  under- 
going longitudinal  division,  prove  that  this  method  of  reproduction,  typical  of 
the  Protozoa,  occurs  in  this  parasite.  The  presence  of  a  terminal  flagellum  at 
one  extremity  of  the  organism  is  evident  in  well-stained  specimens. 

In  fresh  specimens  of  blood  this  organism  is  very  actively  motile,  passing 
across  the  microscopic  field  so  rapidly  as  to  be  hardly  distinguishable,  and  this 
rapid  motility  may  be  retained  for  days  and  even  weeks  after  the  blood  has  been 
removed  from  the  body,  but  sooner  or  later,  the  motion  becomes  more  sluggish 
and  it  is  possible  to  study  its  characteristics.  The  active  motion  is  due  to  cork- 
screw-like movements  of  the  parasite  which  enable  it  to  progress  rapidly,  but  as 
the  organisms  become  less  motile  this  form  of  motion  is  succeeded  by  undula- 
tory  movements  of  the  body,  the  resulting  motion  being  slowly  progressive.  In 
organisms  which  have  been  kept  outside  of  the  body  for  weeks,  progressive 
motion  is  lost,  being  succeeded  by  a  swaying  motion  from  side  to  side  and 
slight  twitching  movements  of  the  body.  Careful  observation  will  demonstrate 
that  the  extremities  of  the  body  possess  the  power  of  bending  to  almost  an  acute 
angle,  and  organisms  are  observed  in  which  the  extremities  are  apparently 
united,  a  perfect  circle  thus  being  formed. 

Spirochaeta  Duttoni  (Spirillum  Duttoni). — The  disease  due  to  this 
parasite,  or  tick  fever,  was  first  described  by  Livingstone,  but  it  was  not  until 
the  discovery  of  a  spirochaeta  in  the  blood  of  patients  suffering  from  it,  by  Ross 
and  Milne,  in  1904,  and  almost  simultaneously  by  Dutton  and  Todd,  that  the 
etiology  of  the  disease  was  placed  upon  a  scientific  basis.  It  is  probable  that 
this  spirochaeta  has  been  more  thoroughly  studied  than  any  of  this  class  of 
organisms  and  yet  the  biological  position  of  the  organism  is  undetermined 
and  the  morphological  data  variously  interpreted  by  different  observers. 

In  length  Spirochaeta  duttoni  varies  frcm  13^  to  45//  and  in  width  from 
0.2/1  to  o.4/t.  Different  authorities  give  very  different  measurements,  Novy  and 
Knapp  stating  the  length  as  16/*;  Dutton  and  Todd  as  13/i  to  43^;  Ross  as 
45/i,  and  Schellach  as  2411.  It  is  probable  that  some  of  the  longer  measure- 
ments were  obtained  by  measuring  two  organisms  attached  end  to  end,  as  they 
so  frequently  are.  The  morphology  is  similar  to  that  of  Spirochaeta  recurrentis, 
a  flagellum  being  present  at  one  end  and  the  staining  being  irregular  when 
Giesma's  stain  is  employed.  Transverse  and  longitudinal  division  occurs, 
transverse  division  being  the  usual  method  of  reproduction.  The  motility  of  this 
species  is  greater  than  that  of  any  other  species  of  spirochaetae  found  in  man. 

The  observations  of  Dutton  and  Todd  upon  the  morphology  of  this 
organism  and  those  of  Schellach  are  especially  important  and  demand  atten- 


THE    BLOOD    PROTOZOA    OF    MAN.  449 

tion.  Dutton  and  Todd  state  that  the  organism  is  ribbon-shaped  on  transverse 
section,  and  that  it  is  composed  of  a  central  core  staining  a  deep  red,  the  chroma- 
tin, and  of  a  delicate  periplastic  sheath,  staining  light  pink.  Both  extremites 
are  pointed,  but  one  may  be  extended  through  the  sheath  as  aflagellum,  which 
contains  no  chromatin.  The  chromatin  may  not  stain  as  a  solid  core,  but  may 
lie  in  irregular  masses  surrounded  by  unstained  areas.  Peritrichial  flagella 
were  never  observed.  Many  of  the  spirochaetae  presented  deeply  stained  knobs 
or  swellings,  either  situated  at  one  end  or  laterally,  some  of  them  being  separated 
from  the  parent  organism,  but  still  attached  by  a  very  delicate  pink-staining 
thread.  Most  of  these  swellings  stain  uniformly  red,  but  in  some  the  protoplasm 
is  stained  blue  and  contains  deep  red  dots  of  chromatin. 

Some  of  the  organisms  are  thicker  at  one  extremity  than  at  the  other  and 
these  forms  the  authors  believe  to  indicate  a  stage  preceding  longitudinal 
division.  The  usual  method  of  reproduction  was  found  to  be  by  transverse 
division,  but  longitudinal  division  was  frequently  observed,  being  most  common 
toward  the  termination  of  the  attack.  Longitudinal  division  is  preceded  by 
thickening  of  the  organism  which  then  splits,  beginning  at  one  end,  thus  pro- 
ducing the  Y-shaped  forms  frequently  observed.  In  smears  made  from  the 
spleen,  bone-marrow,  and  liver,  the  spirochaetae  were  frequently  observed 
coiled  up  into  spherical  masses,  which  become  larger  and  irregular  in  shape  as 
the  crisis  approaches.  Interesting  changes  were  observed  in  some  of  these 
organisms,  consisting  in  encystment  followed  by  disintegration  of  the  body  of 
the  parasite,  the  cyst  being  filled  with  granules  showing  the  chromatin  staining 
reaction.  They  note  the  occurrence  of  minute,  blue-stained  bodies,  containing 
chromatin  granules,  and  measuring  from  r/i  to  3//  in  diameter,  in  the  blood  and 
organs  of  infected  animals,  but  are  uncertain  of  the  nature  of  such  bodies. 
These  authors  agree  with  Leishman  that  Spirochaeta  duttoni  possesses  an 
undulating  membrane,  stating  that  they  have  observed,  both  in  the  blood  of 
men  and  animals,  and  in  blood  from  the  alimentary  canal  of  the  tick,  an  un- 
mistakable undulating  membrane.  To  demonstrate  it  they  recommend  the 
use  of  the  highest  powers  and  a  very  careful  scrutiny  of  every  organism.  This 
membrane  extends  the  entire  length  of  the  body  and  some  of  the  unstained 
areas  in  the  latter  are  due  to  the  undulating  membrane  crossing  the  body. 

Schellach  observed  the  spirochaeta  in  the  living  state.  He  gives  the 
length  as  24/i  at  the  most,  the  width  as  0.45//.  The  number  of  undulations  as 
8  to  12.  A  terminal  flagellum  was' demonstrated,  but  while' he  obtained  peri- 
trichial flagella  by  Zettnow's  method,  he  regards  them  as  artefacts.  Deep- 
staining  granules  were  noted  in  the  protoplasm  when  Giemsa's  method  of  stain- 
ing was  employed.  He  also  described  appearances  suggesting  longitudinal 
division,  but  considers  that  the  method  of  reproduction  is  always  by  transverse 
division.  While  Dutton  and  Todd  claim  that  the  organism  may  occur  both 
within  red  and  white  blood-corpuscles,  Schellach  believes  that  the  organisms 
are  not  intracellular  at  any  stage  of  development  and  that  phagocytosis  does  not 
occur. 

2Q 


45° 


THE    BLOOD    PROTOZOA    OF    MAN. 


Breinl,  Kinghorn,  and  Garrett  could  not  demonstrate  an  undulating  mem- 
brane or  a  flagellum,  but  they  describe  refractile  dots  in  the  protoplasm. 

The  motility  of  Spirochacta  duttoni  is  similar  in  character  to  that  oi  Spiro- 
chaeta recurrentis,  consisting  in  cork-screw  motions,  undulations,  and  a  swaying 
motion,  but  it  is  much  more  active  than  any  of  the  other  spirochaetae  of  man. 

Spirochaeta  novyi  (Spirillum  novyi). — This  spirochaeta  resembles  in  its 
general  morphological  characters  the  organisms  already  described,  but  it  is 
shorter  and  more  slender  than  the  other  spirochaetae  of  man.  The  organism 
has  been  thoroughly  studied  by  Norris,  Novy,  and  Knapp  and  more  recently 
by  Schellach. 

Ai  cording  to  Novy  and  Knapp,  single  cells  of  this  organism  measure  from 
lix  to  q«  while  Schellach  gives  the  length  as  from  17/x  to  20LI  with  6  to  8  undula- 
tions. The  same  author  gives  the  width  as  0.31//.  A  terminal  flagellum  has 
been  demonstrated  by  Novy,  Knapp,  and  Schellach,  and  while  peritrichial 
iiagella  have  been  described  by  Fraenkel  and  Zettnow,  it  is  generally  conceded 
that  these  were  artefacts  produced  by  the  method  of  staining.  The  organism 
is  actively  motile,  the  same  varieties  of  motion  being  observed  as  in  the  preced- 
ing spirochaetae.  Reproduction  occurs  by  transverse  division,  but  longitudinal 
division  occurs  at  certain  intervals,  typical  dividing  forms  having  been 
observed. 

Spirochaeta  carteri  (Spirillum  carteri). — As  described  by  Mackie, 
Spirochaeta  carteri  measures  from  12 11  to  16/i  in  length,  by  00.3/i  to  0.5/1  in 
breadth,  but  forms  are  observed  measuring  from  7/1  to  8/j.,  while  in  infected  lice 
the  spirochaetae  may  measure  only  2ll  to  3/*  in  length.  Only  in  degenerative 
forms  has  any  trace  of  structure  been  discovered,  the  appearance  of  chromatin 
dots  being  coincident  with  degeneration  of  the  cytoplasm.  A  terminal  flagel- 
lum is  demonstrable,  but  Mackie  interprets  this  as  the  empty  portion  of  the 
sheath  which  surrounds  the  organism.  Transverse  division  is  the  common 
method  of  reproduction,  but  Mackie  has  observed  organisms  in  the  stomach  of 
the  louse  which  were  probably  undergoing  longitudinal  division  and  con- 
jugation. An  undulating  membrane  has  not  been  demonstrated.  The 
organism  is  motile,  the  movements  being  similar  in  character  to  those  described 
in  the  other  spirochaetae  of  man. 

From  the  descriptions  of  the  spirochaetae  given  it  will  be  observed  that 
their  differentiation  upon  morphological  grounds  alone  rests  upon  the  size,  the 
number  of  undulations  or  curves,  and  the  character  of  the  curves.  The  follow- 
ing table  illustrates  the  variations  in  these  particulars  in  the  four  species  of 
spirochaetae  which  infect  man: 


Length    Max . 

Width     

No.  of  Curves 
Shape  of  Curves 


Sp.  recurrentis 


19/1  to  29/x 

8  to  10 
spiral 


Sp.  duttoni 


I  2fJL  to  24// 

0.45/^ 
8  to  12 
open  flexures 


Sp.  novyi 


1-jjj.  to  20/! 
0.3  i/i 
6  to  8 
typical  spirals 


Sp.  carteri 


l6fl 
0.50  ft 

(?) 
open  flexures 


THE    BLOOD    PROTOZOA    OF    MAN.  45 1 

Mackie  considers  that  Sp.  Carteri  can  be  easily  distinguished  upon  morpho- 
logical grounds  from  Sp.  novyi,  the  latter  being  shorter,  staining  less  intensely, 
and  thinner  and  more  delicate  in  contour;  the  American  organism  being 
typically  spiral  in  shape,  the  Asiatic  having  very  shallow  undulations,  more  open 
in  character. 

Fortunately,  we  do  not  have  to  depend  upon  morphology  in  order  to  differ- 
entiate the  spirochaetae,  for  we  possess  in  their  reactions  to  immune  sera  and  to 
inoculation  into  various  animals,  a  certain  and  easy  method  of  distinguishing 
them. 

Cultivation  of  Spirochaetae. — Spirochaeta  novyi  is  the  only  spirochaete 
which  has,  at  the  present  writing,  been  cultivated  upon  artificial  media  outside 
of  the  human  body.  Novy  and  Knapp  succeeded  in  cultivating  the  organisms 
in  collodiun  sacs  placed  in  the  peritoneal  cavity  of  white  rats,  and  in  this  manner 
they  were  able  to  carry  the  parasites  through  successive  generations,  multiplica- 
tion being  abundant.  Their  method  was  as  follows:  "Collodium  sacs  were 
filled  with  uncoagulated  rat's  blood  and  after  inoculation  were  placed  at  once  in 
the  peritoneal  cavity  of  a  white  rat.  Three  days  later,  on  removal,  the  sacs 
were  found  to  contain  active  spirilla  and  in  increased  numbers.  From  the  sacs 
transplants  were  made  to  new  ones  and  the  result  was  equally  satisfactory." 
They  transplanted  their  cultures  every  three  or  four  days,  using  sacs  containing 
from  2.5  to  3  ex.,  and  it  was  found  that  if  the  sacs  were  left  in  the  perito- 
neal cavity  for  seven  days  or  over  the  spirochaetae  decreased  in  number  or 
disappeared. 

The  spirochaetae  of  all  of  the  relapsing  fevers  may  be  kept  alive  for  days 
and  weeks  in  citrated  blood  at  room  temperature,  but  there  is  no  evidence  that 
multiplication  occurs,  and  transplants  cannot  be  obtained. 

The  morphology  of  the  spirochaetes  in  the  collodium  sacs  did  not  differ 
from  that  of  the  organisms  in  the  blood,  and,  according  to  Novy  and  Knapp, 
there  was  no  evidence  of  a  developmental  cycle  in  their  cultures  similar  to  that 
demonstrated  in  some  of  the  protozoa. 

Butler  has  recently  shown  that  in  citrated  blood,  kept  in  an  ice-box  at  a 
temperature  of  i5°C,  Spirochaeta  duttoni  develops  oval  or  round  enlargements, 
situated  either  at  the  extremities  or  laterally,  which  contain  granules  of  chroma- 
tin. The  parent  body  degenerates  after  from  two  to  three  months,  but  the 
enlargements  retain  the  stain  and  become  free  in  the  plasma.  Butler  found 
the  same  bodies  upon  spirochaetes  in  blood  obtained  from  the  stomach  of 
fleas  allowed  to  feed  upon  infected  rats.  These  bodies  are  the  same  as  those 
previously  described  by  Dutton  and  Todd  as  occurring  upon  Spirochaeta  duttoni 
observed  in  the  blood  of  infected  rats.  In  our  work  upon  Treponema  pertenue  and 
Treponema  pallidum,  Ashburn  and  myself  observed  similar  bodies  attached  to 
both  these  organisms,  and  the  fact  that  they  are  observed  so  frequently  is  very 
suggestive  that  they  have  something  to  do  with  the  reproduction  of  both  spiro- 
chaeta and  treponema. 

Pathogenicity. — The  group  of  fevers  caused  by  the  spirochaetes  described 


45 2  THE    BLOOD    PROTOZOA    OF    MAN. 

are  characterized  by  attacks  of  fever  alternating  with  periods  of  normal  tem- 
perature. At  the  time  of  pyrexia  the  organisms  are  found  in  the  peripheral 
blood,  but  become  less  numerous  during  the  decline  in  the  fever,  and  after  the 
crisis  they  entirely  disappear  from  the  peripheral  blood,  although,  as  shown  by 
Breinl  and  Kinghorn,  in  the  case  of Spirochaeta  duttoni,  the  blood  is  still  infective 
to  susceptible  animals.  These  parasites  are  pathogenic  for  some  of  the  lower 
animals,  and  the  reaction  of  these  animals  to  the  inoculation  of  the  different 
species  and  the  reaction  of  the  organisms  to  immune  sera  form  our  most  effi- 
cient methods  of  differentiating  the  various  species. 

Spirochaeta  recurrentis  is  pathogenic  for  man,  monkeys,  white  rats, 
tame  rats,  and  mice.  In  monkeys  the  injection  of  blood  containing  this 
organism  is  followed  by  severe  fever,  accompanied  by  relapses,  and  the  parasite 
is  easily  demonstrated  in  large  numbers  in  the  peripheral  blood.  White  rats 
and  mice  can  only  be  infected  by  the  inoculation  of  organisms  which  have  first 
been  passed  through  the  monkey,  and  antibodies  are  formed  in  the  blood  of 
infected  animals.  To  Uhlenhuth  and  Haendel  and  Fulleborn  and  Meyer  we 
owe  much  cf  our  knowledge  of  the  pathogenic  properties  of  this  spirochaeta. 

Spirochaeta  duttoni  is  pathogenic  for  man,  monkeys,  white  rats,  common 
rats,  mice,  guinea-pigs,  rabbits,  dogs,  sheep,  horses,  and  goats,  while  cats, 
pigeons,  and  chickens  are  not  susceptible.  The  researches  of  Breinl  and 
Kinghorn  upon  the  pathogenicity  of  this  organism  are  most  valuable.  They 
found  that  the  white  rat  is  more  susceptible  to  infection  than  is  the  monkey, 
and  that  the  parasite  passes  through  the  placenta,  thus  infecting  the  foetus. 
They  also  determined  that  it  passes  through  a  Berkefeld  filter  fine  enough  to 
retain  B.  prodigiosan.  In  their  work  the  period  of  incubation  varies  from  a 
few  hours  in  white  rats  to  seven  days  in  monkeys,  and  relapses  occurred  in  most 
of  their  experimental  animals.  (The  occurrence  of  relapses  at  regular  intervals 
following  infection  with  the  spirochaetae  is  very  significant  of  their  protozoal 
nature,  as  they  indicate  that  the  organism  passes  through  a  definite  cycle  of 
development.)  The  disease  in  monkeys  is  not  generally  fatal,  but  in  white 
rats  and  guinea-pigs  a  fatal  result  is  frequent.  These  observers  also  demon- 
strated that  the  peripheral  blood  is  infective  during  apyrexia,  although  the 
spirochaeta  cannot  be  found  in  it,  which  would  appear  to  prove  that  during 
apyrexia  the  parasite  is  present  in  the  blood  in  some  form  which  has  not  yet 
been  recognized. 

Spirochaeta  novyi  is  pathogenic  for  man,  monkeys,  white  rats  and  mice, 
and  tame  and  wild  rats.  Novy  and  Knapp  found  that  white  mice  were  very 
susceptible,  and  that  the  organisms  occurred  in  their  blood  in  immense  numbers. 
These  observers  found  that  rabbits  and  guinea-pigs  could  not  be  infected. 

Spirochaeta  carteri  has  been  found  by  Mackie  to  be  pathogenic  for 
white  rats  and  mice,  white  rabbits,  black  rats,  brown  rats,  and  guinea-pigs. 
Goats,  dogs,  cats,  and  pigeons  are  not  susceptible.  As  with  the  other  spiro- 
chaetes,  this  organism  is  pathogenic  to  man  and  monkeys.  The  disease  in 
laboratory  animals,  except  the  monkey,  is  of  slight  character,  and  the  organisms 


THE    BLOOD    PROTOZOA    OF    MAN.  453 

occur  in  the  blood  in  small  numbers.  Mackie  found  that  the  monkey  could 
be  infected  by  scarification  of  the  skin  followed  by  the  rubbing  in  of  infected 
blood;  by  feeding  with  blood  containing  the  organisms,  and  by  puncture  of  the 
skin  with  a  grooved  needle  containing  the  virtus. 

Immunity. — From  a  diagnostic  and  therapeutic  standpoint  the  question 
of  acquired  immunity  to  infection  with  the  various  species  of  spirochaetae  is  of 
great  importance,  but  as  yet  an  immune  serum  which  can  be  used  for  the 
treatment  of  human  infections  has  not  been  produced,  although  Novy  and 
Knapp  have  cured  infections  in  rats  by  the  injection  of  immune  blood.  It  is 
a  fact  of  prime  importance  in  the  differential  diagnosis  of  the  species  of  spiro- 
chaetae that  an  animal  which  has  suffered  from  an  infection  with  one  species  is 
immune  to  that  species  but  not  to  the  others,  so  that  a  differential  diagnosis  is 
easily  made  by  the  use  of  immune  animals.  The  occurrence  of  any  of  the 
varieties  of  relapsing  fever  in  man  is  followed  by  a  period  of  immunity,  and  this 
is  also  true  of  experimental  infections  in  the  lower  animals,  but  the  duration  of 
the  immune  period  is  not  known  and  varies  with  the  species  of  animal  and  the 
species  of  spirochaeta  producing  the  infection. 

The  immunity  produced  by  Spirochaeta  recurrentis  is  slight  and  transient 
in  character.  Immune  substances  are  produced  in  the  blood  of  animals  suffer- 
ing from  the  infection,  and  blood  serum  containing  them  causes  paralysis  of 
movement  in  this  spirochaeta,  but  has  no  effect  upon  the  other  spirochaetae. 
Metchnikoff 's  theory  that  the  disappearance  of  the  spirochaetae  from  the  blood 
was  due  to  phagocytosis  occurring  principally  in  the  spleen  has  been  disproven 
by  Tictin,  Lamb,  and  Breinl  and  Kinghorn. 

Breinl  and  Kinghorn,  working  with  Spirochaeta  duttoni,  were  unable  to 
produce  immunity  by  immune  serum  or  to  cure  the  infection  in  animals  by 
'the  use  of  such  serum.  Their  conclusions  are  of  great  value  and  are  given 
practically  verbatim: 

i.  "Immune  serum,  whether  derived  from  horses,  monkeys,  or  rats,  has  no 
appreciable  value  either  in  preventing  the  occurrence  of  the  attacks  in  suscep- 
tible animals  or  in  curing  the  disease  once  contracted.  The  incubation  period 
may  be  prolonged  to  a  greater  or  less  extent,  but  the  inoculation  of  infected 
blood  is  always  followed  by  infection. 

2.  "Hyperimmune  serum  has  no  pronounced  value  in  the  treatment  of  the 
disease  in  monkeys,  does  not  prevent  infection,  but  given  in  large  doses  markedly 
lengthens  the  incubation  period,  and  mitigates  the  course  of  the  disease. 

3.  "In  animals  which  have  recovered  from  the  infection  there  is  a  rel- 
atively active  immunity  of  comparatively  long  duration. 

4.  "We  have  been  unable  to  produce  passive  immunity  through  the  use 
of  immune  serum. 

5.  "In  animals  from  which  the  spleen  has  been  removed,  the  spirochaetes 
disappear  from  the  peripheral  circulation  after  the  attack  as  promptly  as  in 
normal  animals,  and  relapses  occur  in  the  ordinary  way." 

These  authors  also  proved  that  animals  rendered  immune  to  infection 


454  THE    BLOOD    PROTOZOA   OF    MAN. 

with  Spirochaeta  duttoni,  because  of  having  recovered  from  such  infection, 
were  not  immune  to  Spirochaeta  recurrentis,  and  that  ticks  fed  upon  infected 
animals  were  able  to  transmit  the  infection  immediately. 

The  immunity  produced  by  infection  with  Spirochaeta  novyi  has  been 
carefully  studied  by  Novy  and  Knapp,  whose  conclusions  are  here  reproduced 
in  part: 

i.  "A  powerful  specific  germicidal  body  is  present  in  the  decline  and  in 
recovered  blood,-  notably  in  blood  of  hyperimmunized  rats.  An  immunizing 
body  is  also  present  and  is  probably  distinct  from  the  germicidal  agent. 

2.  "Pfeiffer's  phenomenon  can  be  demonstrated  in  vitro  and  in  vivo." 

3.  "Active  immunity  follows  recovery  from  the  infection.  By  successive 
injections  of  spirillar  blood  this  immunity  can  be  increased  to  a  remarkable 
degree." 

4.  "Passive  immunity  can  be  imparted  by  injections  of  recovered  or 
hyperimmunized  blood." 

5.  "Preventive  inoculations  can  be  successfully  made  in  rats,  mice,  and 
monkeys." 

6.  "Infected  rats,  mice,  and  monkeys  can  be  promptly  cured  by  injection 
of  hyperimmunized  blood." 

7.  "Agglutination  of  spirilla  occurs  in  vitro  and  in  vivo  under  the  influence 
of  recovered  or  hyperimmunized  blood." 

8.  "The  agglutination,  germicidal,  and  immunizing  properties  of  recovered 
blood  can  be  used  in  the  sero-diagnosis  of  relapsing  fever.  Also  for  the  identifi- 
cation of  spirilla." 

From  the  results  obtained  by  Novy  and  Knapp  it  is  evident  that  this 
organism  differs  very  greatly  from  Spirochaeta  duttoni  in  its  effect  upon  animals, 
for,  as  shown  by  Breinl  and  Kinghorn,  the  latter  produces  no  immune  serum 
capable  of  preventing  or  curing  an  infection,  while  a  very  active  immunizing 
and  curative  serum  is  produced  after  infection  with  Spirochaeta  novyi. 

According  to  Mackie,  the  injection  of  blood  from  man  and  monkeys 
containing  Spirochaeta  carteri  into  monkeys  and  goats  is  followed  by  a  certain 
degree  of  immunity,  and  the  blood  serum  from  these  animals  killed  the  spiro- 
chaetes  within  fifteen  seconds  in  a  dilution  of  1  in  20. 

Methods  of  Transmission. — -It  is  now  generally  believed  that  all  the 
species  of  spirochaetae  producing  relapsing  fever  in  man  are  transmitted  through 
the  agency  of  insects,  and,  in  the  instance  of  the  relapsing  fever  of  Africa,  or 
"tick  fever,"  this  method  of  transmission  has  been  definitely  proven. 

Spirochaeta  recurrentis  is  believed  to  be  transmitted  by  an  insect,  but  we 
possess  no  definite  knowledge  as  to  what  insect  is  concerned,  although  the  bed- 
bug {Cimex  lectularius)  has  been  regarded  by  some  observers  as  the  transmitting 
agent.  As  long  ago  as  1897,  Tictin  concluded,  as  the  result  of  his  experiments, 
that  this  bug  transmitted  the  disease.  He  allowed  bed-bugs  to  suck  the  blood 
from  patients  suffering  from  relapsing  fever,  then  rubbed  them  up  in  a  mortar 
and  inoculated  them  into  monkeys,  which  afterward  developed  fever.     His 


THE    BLOOD    PROTOZOA    OF    MAN.  455 

experiments  were  obviously  imperfect  as  regards  technic  and  the  more 
recent  negative  experiments  of  Breinl  and  Kinghorn  with  these  bugs  and  both 
Spirochaeta  recurrentis  and  Spirochaeta  duttoni  prove  that  the  bed-bug  does  not 
transmit  these  parasites  to  man. 

The  method  of  transmission  of  Spirochaeta  duttoni  has  been  definitely 
ascertained.  Dutton  and  Todd,  working  in  the  Congo  valley,  proved  that 
African  tick  fever  is  due  to  the  organism  that  we  now  know  as  Spirochaeta 
duttoni,  and  that  it  is  transmitted  to  man  by  the  bite  of  a  tick,  Ornithodorus 
moubata,  which  had  sucked  the  blood  of  infected  individuals.  These  observers 
also  proved  that  the  infection  in  the  tick  is  hereditary,  as  the  larvae  hatched  out 
of  the  eggs  of  infected  ticks  were  also  capable  of  causing  the  disease.  Their 
observations  were  at  once  confirmed  by  Ross  and  Milne,  and  later  by  Breinl 
and  Kinghorn,  and  there  can  be  no  doubt  but  that  this  organism  is  conveyed  to 
man  by  the  bites  of  infected  ticks  or  their  progeny. 

Dutton  and  Todd  have  studied  very  carefully  the  morphological  changes 
occurring  in  Spirochaeta  duttoni  in  the  tick,  Ornithodorus  moubata.  Many 
degenerating  forms  are  observed  in  the  blood  in  the  stomach  of  the  tick  after  it 
has  bitten  an  infected  animal,  as  well  as  all  of  the  forms  described  as  occurring 
in  the  peripheral  blood.  In  blood  from  the  receptaculum,  obtained  24  hours 
after  ingestion,  they  observed  two  distinct  types  of  organism,  one  slender  and 
the  other  stout,  while  a  third  form  was  seen  rarely,  which  was  twice  the  usual 
length  and  three  times  the  usual  breadth.  The  organisms  were  also  observed 
coiled  up  within  erythrocytes,  leucocytes,  and  within  the  cells  lining  the  receptac- 
ulum, while  encysted  forms  were  very  common.  Fragmentation  of  the  chro- 
matin was  very  marked  and  only  a  single  granule  is  found  in  the  encysted  form. 
At  a  later  stage  of  development  the  granules  are  double,  the  parasite  consisting 
of  a  blue-stained  mass  of  protoplasm  containing  many  pairs  of  deep  red  granules. 
They  were  not  able  to  follow  the  further  development  of  these  bodies,  but  sug- 
gest that  they  rupture,  setting  free  the  chromatin  pairs,  which  eventually 
develop  into  minute  spirochaetes.  In  stained  specimens  they  believe  that  they 
have  been  able  to  trace  the  development  of  a  single  granule  into  a  comma- 
shaped  clump  of  chromatin  from  which  a  small  spirochaete  developed.  These, 
observations  have  not  been  confirmed. 

Koch  studied  the  organisms  in  the  stomach  of  the  tick  and  was  unable  to 
trace  any  cycle  of  development.  He  found  that  the  spirochaetae  disappeared 
from  the  stomach  in  a  few  days  and  could  then  be  found  upon  the  surface  of  the 
ovary,  where  multiplication  occurred.  Carter  describes  longitudinal  division 
as  occurring  in  spirochaetes  of  this  species  in  the  eggs  of  ticks,  but  this  observa- 
tion still  awaits  confirmation.  We  do  not  know  anything  as  yet  regarding  the 
method  of  transmission  to  man  of  Spirochaeta  novyi. 

Mackie  has  endeavored  to  demonstrate  the  method  of  transmission  of 
Spirochaeta  carteri,  and  his  results  would  appear  to  indicate  that  the  common 
body  louse  (Pediculus  corporis)  is  capable  of  transmitting  this  parasite  to  man. 
He  found  that  14  per  cent,  of  lice  taken  from  a  badly  infected  boy's  ward,  2 


456  THE    BLOOD    PROTOZOA    OF    MAN. 

per  cent,  from  a  slightly  infected  girl's  ward,  and  13  per  cent  of  lice  fed  upon 
infected  patients,  showed  spirochaetes  in  the  stomach  blood  and  in  the  ovaries, 
multiplication  of  the  organisms  having  occurred  in  both  stomach  and  ovaries. 
He  states  that:  "A  fluid  rich  in  active  spirilla  (spirochaetes)  could  be  obtained 
by  gentle  pressure  on  the  heads  of  infected  lice."  Mackie  also  examined  the 
organs  of  Cimex  rotundatus  and  found  the  spirochaetes  present  in  the  stomach 
until  the  sixth  day  after  feeding,  but  there  was  no  evidence  that  they  underwent 
multiplication.  He  allowed  bugs  of  this  species,  after  biting  infected  monkeys, 
to  bite  10  healthy  monkeys,  but  the  disease  appeared  in  only  one  of  these 
animals,  and  the  infection  in  this  case  may  have  been  due  to  other  factors. 

Distribution  in  Man. — The  spirochaetes  causing  the  relapsing  fevers  are 
blood  parasites  and  are  found  only  in  the  blood  plasma,  as  they  are  not  intracel- 
lular organisms.  The  observations  of  Dutton  and  Todd,  which  would  indicate 
that  these  organisms  occur  within  the  red  blood-corpuscles  and  the  leucocytes, 
have  not  been  confirmed,  and  their  occurrence  in  these  cells  is  probably  acci- 
dental. The  organisms  are  also  found  in  the  capillaries  of  the  various  viscera 
after  death,  but  only  in  a  few  instances  have  they  been  reported  as  occurring 
in  the  endothelial  cells  and  the  cells  of  the  tissues. 

The  examination  of  the  blood  in  relapsing  fever  is  generally  useless  (so 
far  as  demonstrating  the  parasite  is  concerned)  during  apyrexia,  and  even  when 
fever  is  present  several  stained  preparations  should  be  examined  before  the 
result  is  regarded  as  negative. 

Spirochaeta  recurrentis  is  found  only  in  the  blood  stream  during  the  febrile 
paroxysm,  rapidly  disappearing  as  the  crisis  approaches,  and  being  entirely 
absent  from  the  peripheral  circulation  after  the  crisis  occurs. 

Spirochaeta  didtoni  also  occurs  only  in  the  blood  stream,  but  in  smaller 
numbers  than  the  preceding  parasite,  and,  according  to  Ross,  they  can  only  be 
found  during  the  relapse,  being  absent  from  the  peripheral  blood  during  the 
primary  attack.  Dutton  and  Todd  describe  this  parasite  as  occurring  within 
the  erythrocytes  but  their  occurrence  in  this  situation  is  accidental. 

Spirochaeta  novyi  and  Spirochaeta  carteri  also  occur  only  within  the  blood, 
and  in  both  infections  the  organisms  can  be  easily  demonstrated  in  the  peripheral 
blood  during  the  febrile  attack.  In  the  internal  organs  the  parasites  occur 
within  the  capillaries  but  not  within  the  tissue  cells. 

While  the  parasites  cannot  be  demonstrated  in  the  peripheral  blood  during 
the  afebrile  period,  Dutton  and  Todd  have  shown,  in  the  case  of  Spirochaeta 
duttoni,  that  the  apyrexial  blood  is  infective,  and  Mackie  has  shown  that  the 
apyrexial  blood  from  monkeys  infected  with  Spirochaeta  carteri,  produces  in- 
fection in  other  monkeys,  so  that  it  is  more  than  probable  that  the  spirochaetes 
exist  in  the  blood  during  apyrexia  in  some  unrecognized  form,  as  the  examina- 
tion of  scores  of  blood  films  at  this  time  always  results  negatively.  We 
possess  no  evidence  sufficient  to  prove  that  any  of  the  spirochaetes  causing 
relapsing  fever  in  man  are  intracellular  organisms,  all  of  the  observations 
pointing  to  their  being  true  parasites  of  the  blood  plasma.     In  this  they  differ 


THE    BLOOD    PROTOZOA    OF    MAN.  457 

from  Treponema  pallidum  and  Treponema  pertenue,  closely  related  organisms, 
which"  are  true  tissue  parasites. 

Demonstration  of  Spirochaetae. — Spirochaeta  recurrentis,  Spirochaeta 
novyi,  and  Spirochaeta  carteri  may  be  easily  demonstrated  in  fresh  blood 
preparations  from  patients  suffering  from  relapsing  fever,  provided  the  blood 
be  obtained  during  the  febrile  period,  but  after  the  crisis  the  parasites  disappear, 
and  it  is  then  useless  to  examine  the  blood.  Spirochaeta  duttoni  may  also  be 
demonstrated  in  the  fresh  blood  specimens  during  the  febrile  period,  but  this 
organism  occurs  in  such  small  numbers  that  it  is  better  to  make  blood  smears 
and  stain  them  by  some  modification  of  the  Romanowsky  method.  In  fact, 
in  suspected  cases  of  infection  with  any  of  the  spirochaetes  of  relapsing  fever 
better  results  will  be  obtained  by  the  examination  of  stained  blood  smears.  If 
it  is  desired  to  examine  fresh  blood  the  ear  or  finger  should  be  pricked  with  a 
sterilized  needle  and  a  rather  large  drop  of  blood  be  placed  upon  the  microscopic 
slide  and  immediately  covered  with  a  cover-glass.  It  is  necessary  that  the  blood 
film  be  rather  thick,  as  otherwise  the  organisms,  being  comparatively  few  in 
number,  might  be  overlooked.  If  it  is  desired  to  examine  stained  smears  of 
blood  they  should  be  made  rather  thick,  and  should  be  fixed  and  stained  as 
recommended  in  the  section  of  this  work  dealing  with  the  staining  of  the  malarial 
Plasmodia.  Any  modification  of  the  Romanowsky  stain  may  be  employed,  but 
the  Wright  stain,  used  as  recommended  for  the  plasmodia,  gives  the  best 
results.  In  infections  with  Spirochaeta  duttoni,  and  in  other  infections  in  which 
the  spirochaetes  are  few  in  number,  it  is  often  necessary  to  centrifuge  the  blood 
and  examine  the  sediment,  either  as  a  fresh  preparation  or  stained  in  the  same 
manner  as  blood  smears.  The  method  of  centrifugation  is  the  same  as  recom- 
mended for  the  demonstration  of  Trypanosoma  gambiense.  In  both  fresh  and 
stained  specimens  the  spirochaetae  are  easily  recognized,  as  no  other  object 
occurs  in  the  blood  which  in  the  least  resembles  them,  with  the  exception  of 
the  free  flagella  of  the  malarial  plasmodia,  and  to  one  who  has  had  any  ex- 
perience in  the  study  of  malarial  blood,  it  is  easy  to  differentiate  the  flagella 
from  the  spirochaetes. 

In  order  to  differentiate  the  species  of  spirochaetae  we  must  depend  upon 
their  morphology,  their  action  upon  animals,  and  their  reaction  to  immune 
sera.  I  have  already  spoken  of  the  differences  in  the  morphology  of  the  four 
species  described  in  man  and  have  also  noted  for  each  species  the  animals 
to  which  it  is  pathogenic.  The  most  practical  method  of  distinguishing  species 
is  by  the  use  of  immune  blood  sera,  for  it  has  been  found  that  the  serum  of  an 
animal  which  has  suffered  from  infection  with  any  one  of  the  species  has  no 
effect  upon  the  other  species  when  it  is  added  to  blood  containing  them,  but  that 
it  agglutinates  the  species  to  which  the  animal  has  been  rendered  partially  im- 
mune. Therefore,  if  we  possess  blood  serum  from  animals  which  have  been 
infected  with  the  four  species,  we  are  able  to  distinguish  by  the  use  of  these  sera 
any  doubtful  species  with  which  we  are  dealing.  For  instance:  A  spirochaeta  is 
found  in  the  blood,  but  we  are  unable  to  distinguish  the  species  from  morphology 


458  THE    BLOOD    PROTOZOA    OF    MAN. 

alone.  The  blood  serum  of  animals  infected  with  each  of  the  four  species  of 
spirochaetae  is  added  to  blood  from  the  patient  containing  the  spirochaeta, 
and  the  preparation  in  which  agglutination  occurs  contains  the  serum  of  the 
animal  immunized  to  the  spirochaeta  from  the  patient.  Thus,  if  the  spiro- 
chaeta in  the  patient  be  Spirochaeta  duttoni  the  preparation  containing  serum 
from  an  animal  which  has  passed  through  an  infection  with  this  species  will 
be  the  only  one  which  will  show  agglutination  of  the  patient's  spirochaetes. 
In  this  way  it  is  possible  to  demonstrate  with  which  species  we  have  to  deal  in 
cases  in  which  morphology  cannot  be  depended  upon  for  such  differentiation. 

It  is  probable  that  further  research  will  result  in  simpler  methods  of  dif- 
ferentiating species,  for  it  must  be  confessed  that  the  methods  in  which  it  is 
necessary  to  use  animals  are  too  cumbersome  and  difficult  of  application  to  be 
of  much  use  to  the  general  practitioner  in  the  diagnosis  of  the  relapsing  fevers. 


Literature  upon  the  Spirochaetes  of  Relapsing  Fever  of  Man. 

1S73.      Obermeier,   O.      Berl.   klin.    Wochenschrift,   pp.    152-378-391-455. 
1S80.      Megnin.      Les  parasites  et  les  Maladies  parasitaires.      Paris. 

1898.  Gabritschewsky,  G.  Beitrage  zur  Pathologie  u.  Serotherapie  der 
Spirochaten-Infektionen.      Centralbl.  f.   Bakt.,  i,   No.   23,  p.   365. 

1899.  Bardach,  J.  Recherches  sur  la  fievre  re"currente.  Ann.  de  l'lnst 
Pasteur,  No.  13,  p.  365. 

1901.  Graham.      Relapsing  Fever  in  Sumatra.     Jour.  Trop.  Med.,  vol.  i,  No.  6. 

1902.  Karlinski,  J.  Zur  Aetiology  des  Recurrenstyphus.  Centralbl.  f.  Bakt., 
No.  1,  p.  31. 

1902.  Christy,  C.      Spirillum  Fever.      Jour.  Trop.   Med.,  i,  ii. 

1903.  Idem.  Ornithodoros  moubata  and  Tick  Fever  in  Man.  Brit.  Med.  Jour., 
Sept.   19,  p.   652. 

1904.  Idem.      Tick  Fever.      Brit.  Med.  Jour.,  24,  xii,  p.  1726. 

1904.      Powell.      The  Morphology  of  the  Spirillum  of  Relapsing  Fever.      Brit. 

Med.  Jour.,  30,  iv,  p.  1014. 
1904.      Ross  and  Milne.     Tick  Fever.      Brit.  Med.  Jour.,  26,  xi,  p.  1453. 
1904.      Cook.      Relapsing  Fever  in  Uganda.      Jour.  Throp.  Med.,  January,  p.  325. 

1904.  Novy  and  MacNeal.  On  the  Filtration  of  Trypanosomes.  Sixth  Rep. 
Michigan  Acad.  Sciences,  p.  180. 

1905.  Dutton  and  Todd.  The  Nature  of  Tick  Fever  in  the  Eastern  Part  of 
the  Congo  Free  State,  etc.,  Mem.  xvii,  Liverpool  School  of  Tropical 
Med.,  also  Brit.  Med.  Jour.,  Nov.,  ii,  p.  1259. 

1905.     Cropper.      Spirillum  Fever  in  Palestine.      Brit.  Med.  Jour.,  22,  vii,  p.  190. 
1905.      Low.      Discussion  on  Tick  Fever.     Ibid.,  i,  ii,  p.  47. 
1905.      Wellman,  F.   C.      Relapsing  Fever.      Amer.   Med.,   No.    10,  p.    151. 
1905.     Yale-Massey.      Spirillosis  in  Portugese  West- Africa.     Jour.  Trop.  Med., 

August. 
1905.      Borrel  et   Marchoux.     Argas  et  spirilles.     Compt.   rend,   de  la  Soc. 

de  Biol.,  17  mars.,  60,  pp.   540-42. 
1905.      Schaudinn,  F.      Zur  Kenntniss  der  Spirochaete  pallida.      Deutsche  med. 

Wochenschr.,   Oct.   31,  p.    1665. 
1905.      Schaudinn-Hoffmann.     Ibid.   Arb.   a.  d.   kaiserl.   Gesundheitsamte,  22, 

P-  527- 


THE   BLOOD   PROTOZOA   OF    MAN.  459 

1904.     Schaudinn,  F.     Generations-  und  Wirtswechsel  bei  Trypanosomen  und 

Spirochaete.      Arb.   a.  d.   kaiserl.   Gesundheitsamte,   20,   p.   387. 
1906.      Breinl  and  Kinghorn.     Observations  on  the  Animal  Reactions  of  the 

Spirochaeta  of  the  African  Tick  Fever.      Lancet,   March   jo,  p.   668. 
1906.      Breinl,  Kinghorn,  and  Garrett.      Mem.  Liverpool  School  Trop.  Med., 

No.   21. 
1906.      Now  and   Knapp.      Studies  on  Spirillum  Obermeieri  and  Related  Or- 
ganisms.    Jour.  Infec.  Diseases,  May,  vol.  iii,  p.   291. 
1906.     Carlisle,  R.  D.     Ibid.,  p.  233. 

1906.      Norris,  Pappenheimer,  and  Flournoy.     Ibid.,  p.  266. 
1906.     Ross,  P.     Tick  Fever.     Jour.  Trop.,   Med.,  i,  iii. 
1906.      Koch,    Robert.      Vorlaufige    Mitteilungen    iiber    die     Ergebnisse  einer 

Forschungsreise  nach  Ost-  Africa.      Deutsch.  med.  Wochenschr.,  Nov.  23, 

p.  1865. 
1906.      Idem.      Ueber    afrikanischen    Recurrens.      Berl.  klin.  Wochenschr.,  Feb. 

12,  p.  185. 
1906.     Prowazek.      Morphologische,    etc.,  iiber    Hulmerspirochaten    Arb.    a.  d. 

kaiserl.  Gesundheitsamte,    xviii,    p.   554. 
1906.      Zettnow,  E.    Geisselnbei  Huhner- und  Recurrens-Spirochaten.   Deutsche 

med.    Wochenschr.,    March   8,    p.    376. 
1906.      Idem.      Farbung    und  Teilung  bei   Spirochaten.      Zeitschr.  f.  Hyg.,    Bd. 

Hi,  p.  485- 
1906.      Schilling.      Ruckfallfieber.      Hand.    der.    Tropen    Krankheiten.    Mense. 

Bd.  iii,  Halbbd.  ii. 
1906.      Now   and    Knapp.      Spirochaete   Obermeieri.     Am.   Jour.  Med.  Assoc, 

January  13. 

1906.  Idem.  The  Cultivation  of  Spirillum  Obermeieri.  Jour.  Am.  Med.  Assoc, 
Dec.  29,  vol.  xlvii,  p.  21  52. 

1907.  Fulleborn  and  Meyer.      Med.   Klinik,  Apr.   28. 

1907.      Uhlenhuth     and     Haendel.     Arb.    a.    d.    kaiserl.     Gesundheitsamte, 

No.  26. 
1907.      Ross,  Philip.      Tick  Fever.      Allbutt  and  Rolleston's  System  of  Medicine, 

vol.  ii,  Part  ii,  p.   130. 
1907.      McCrae,  T.      Relapsing  Fever.      Osier's  Modern  Medicine,  vol.  ii,  p.  245. 
1907.      Manson,   Sir  P.      Relapsing  Fever.      Tropical  Diseases,  Fourth  Ed.,  p. 

171. 

1907.  Minchin.  The  Protozoa.  Allbutt  and  Rolleston's  System  of  Medicine, 
vol.    ii,    Part    ii,    p.    42. 

1908.  Mackje.  A  Review  of  Recent  Work  on  Spirillar  Fevers.  New  York 
Med.  Jour.,  Aug.  22.     Also  Trans.  Am.  Soc  Tropical  Med.,   1908 

1908.  Dutton  and  Todd.  A  Note  on  the  Morphology  of  Spirochaeta  duttoni. 
Trans.  Soc  of  Tropical  Med.  and  Hyg.,  p.  52. 

1908.      Butler.     U.  S.  Naval  Med.   Bull.,  vol.  ii,  No.  4,  p.   1. 

1908.  Stephens  and  Christophers.  Practical  Study  of  Malaria  and  Blood- 
parasites,  375. 


CHAPTER  IV. 

Histoplasma  Capsulatum. 

In  December,  1905,  Darling  discovered  a  protozoan  organism  in  the 
endothelial  cells  of  the  lung,  spleen,  liver,  and  bone-marrow  to  which  he  gave 
the  name  Histoplasma  capsulation.  While  this  parasite  has  not  been  found  in 
the  peripheral  blood,  and  while  it  is  not,  strictly  speaking,  a  parasite  of  the 
blood,  the  fact  that  it  closely  resembles  in  its  morphology  the  Leishman- 
Donovan  bodies  (Leishmania  donovani)  and  that  it  is  found  within  the  endothe- 
lial cells  in  smears  from  the  liver,  spleen,  and  bone-marrow  is  sufficient  excuse 
for  a  brief  consideration  of  this  interesting  organism  in  any  discussion  of  the 
blood  protozoa.  The  parasite  has  only  been  observed  in  three  patients  at 
autopsy  and  has  never  been  demonstrated  in  living  individuals.  All  of  the 
cases  have  been  observed  by  Darling  upon  the  Isthmus  of  Panama,  the  most 
important  clinical  symptoms  being  an  irregular  remittent  temperature,  spleno- 
megaly, emaciation,  and  a  marked  leucopenia.  The  parasites  were  found  in 
the  endothelial  cells  of  the  lymph  and  blood-vessels,  and  in  necrotic  areas  and 
granuloma-like  growths  in  the  intestine,  the  lymph  nodes,  the  bone-marrow, 
and  the  liver,  spleen,  and  lungs.  It  has  never  been  found  free  in  the  blood 
plasma.  A  similar  organism  has  been  found  by  Darling  in  mucus  from  the 
colon  of  a  rat,  but  it  is  doubtful  if  the  two  are  identical. 

The  following  description  of  the  parasite  is  given  by  Darling  in  his  article 
upon  "Histoplasmosis"  in  "The  Archives  of  Internal  Medicine"  for  September, 
1908. 

"The  bodies  are  round  and  oval.  There  is  among  the  larger  forms  a 
tendency  toward  an  oval  outline.  A.n  average-sized  spherical  body  is  3 
microns  in  diameter.  The  longer  diameter  of  an  oval  body  is  3.75  microns. 
The  bodies  are  always  surrounded  by  a  clear,  refractile,  achromatic  zone  or 
capsule,  giving  the  impression  at  once  of  an  encysted  protozoon.  The  body 
does  not  stain  homogeneously,  but  very  irregularly,  hardly  any  two  parasites 
looking  exactly  alike.  The  body  consists  of  a  deeply  staining  substance  or 
chromatin,  a  faintly  staining  substance  staining  light  blue  with  polychrome 
stains,  and  achromatic  spaces.  The  deeply  staining  substance,  or  chromatin, 
is  practically  always  heaped  up  along  one  side  or  end  of  the  body;  sometimes  it 
consists  of  a  single  mass  or  several  small  masses  of  chromatin;  sometimes  it  is 
ring-shaped  or  occasionally  extending  along  half  of  the  periphery  of  the  body, 
being  crescent-shaped.  Occasionally  a  chromatin  dot  or  very  rarely  a  chroma- 
tin rod  will  be  seen  near  the  larger  chromatin  body.  This  chromatin  dot  or 
chromatin  rod  may  sometimes  be  at  the  opposite  end  or  side  of  the  body. 

460 


THE    BLOOD    PROTOZOA    OF    MAN.  46 1 

There  may  be  several  such  dots  of  chromatin.  When  there  are  several  of  good 
size  the  bodies  appear  to  be  in  a  presegmenting  stage.  The  faintly  staining 
blue  substance  takes  up  the  rest  of  the  space,  excepting  where  there  may  be  one 
or  two  small  achromatic  zones,  resembling  the  vacuoles  of  protozoa.  These 
vacuoles  are  irregularly  disposed,  being  sometimes  in  the  center  and  at  other 
times  near  the  periphery  of  the  body.  The  most  striking  thing  about  the 
parasite  is  the  extremely  irregular  way  in  which  the  staining  substance  (chroma- 
tin) is  disposed.  This  is  in  striking  contrast  with  the  appearance  of  the  Leish- 
man-Donovan  body." 

From  the  above  description  it  is  evident  that  the  parasite  discovered  by 
Darling  is  a  protozoon,  and  that  it  does  not  answer  in  morphology  to  any  of  the 
known  protozoa,  thus  justifying  him  in  placing  it  in  a  new  genus.  Flagellated 
forms  were  observed  in  smears  from  the  lung  in  one  case,  three  organisms 
being  noticed,  each  having  a  single,  short,  thick  fiagellum.  As  many  as  300 
of  the  parasites  were  observed  in  an  alveolar  epithelial  cell  of  the  lung,  and 
many  cells  contained  from  10  to  100  parasites.  The  red  blood-corpuscles  were 
never  invaded. 

The  parasite  is  evidently  very  rare  in  Panama  as  only  three  cases  of  infec- 
tion with  it  have  been  observed  out  of  33,000  admissions  to  the  hospital  at 
Ancon  in  the  Canal  Zone.  Nothing  is  known  as  to  its  method  of  transmission, 
its  endemic  range  or  factors  predisposing  to  infection. 

The  pathological  lesions  peculiar  to  infection  with  Histoplasma  capsulatum 
were  disseminated  hyaline  pseudo-granulomata  in  the  lungs;  necrotic  areas  in 
the  liver,  infiltrated  by  the  parasites;  enlargement  of  the  spleen;  and  ulceration 
of  the  ileum,  jejunum,  and  colon.  The  ulceration  in  the  intestine  appeared  to 
be  preceded  by  the  formation  of  a  circular,  raised  granuloma,  which  became 
pigmented,  and  finally  ulcerated,  the  ulcer  measuring  about  8  mm.  in  diameter. 
It  is  significant  that  ulceration  also  occurs  in  the  intestine  in  infection  with 
Leishmania  donovani,  and  that  both  infections  are  accompanied  by  an  irregular 
fever  and  an  enlarged  spleen. 

Literature  upon  Histoplasma  Capsulatum. 

1906.  Darling,  S.  T.     Jour.  Am.  Med.  Assoc,  xlvi,  p.  1283. 

1907.  Idem.      Histoplasmosis.      Maryland  Med.  Jour.,  April. 

1908.  Idem.  Histoplasmosis.  A  Fatal  Infectious  Disease  Resembling  Kala- 
azar  Found  among  Natives  of  Tropical  America.  Archiv.  Internal 
Med.,  September. 


LIBRARY  OP  run 

ALUMNI  ASSOCIATK 

COLLEGE  OF  PHYSICIANS  AND  SU 
COLUMBIA  UNIVE 
NRW  YORK 

INDEX  OF  AUTHORS 


Abbott,  6,  13,  148,  160 

Addison,  274 

Agramonte,  63 

Albertoni,  380 

Algoni,  347,  359 

Anconi,  380 

Angelini,  102,  116,  175,  267,  282 

Annett,  Dutton,  and  Eliott,  97,  103,  114 

Antolisei,  6,  20,  27,  53,  54,  83,  102,  144, 

175-  363,  368 
Antolisei  and  Angelini,  54,  83,  102,  116, 

175 
Argutinsky,  55 
Arnstein,  138,  146 
Ascoli,  277 

Ashburn,  60,  63,  355,  412 
Askanzy,  129 
Avicenna,  4 

Baccelli,  7,  12,  83,  102,  116,  144,  147, 

223,  363,  376,  407 
Baker,  429 
Balbiani,  247 
Banks,  74 
Banta,  272 
Bar,  273 
Bardach,  458 
Bardelini,  268 
Barker,  134,  148,  160 
Barry,  237 
Bartels,  270,  281 
Bartholow,  296 
Barudel,  240 
Bassett-Smith,  263 
Bastianelli,  6,  7,  8,   13,  20,  32,   58,   59, 

83,  86,  91,  117,  121,  122,  135, 

137,  148,  220,  268,  407 
Bastianelli   and    Bignami,    54,    77,    88, 

116,  121,  135,  217,  268,  407 
Baum,  387 

Bein,  83,  102,  116,  121 
Bell,  262 

Bentley,  411,  425,  426 
Benvenuti,  151 
Berenger-Feraud,  391,  407 
Bernasconi,  141 
Bernheim,  283 
Berthelon,  272,  282 
Berthier,  407 
Bettencourt,  429 
Bettinetti,  347,  359 
Bevans,  292,  297 
Beyer,  145 


Bignami,  6,  7,  8,  12,  13,  20,  32,  34, 
57,  58,  59,  80,  83,  86,  88,  91, 
92,  116,  117,  118,  1 2  j,  122, 
128,  130,  134,  135,  136,  144, 
147,  148,  160,  164,  166,  182, 
220,  244,  268,  277 

Bignami  and  Bastianelli,  54,  55,  268 

Bignami  and  Dionisi,  164,  166 

Billet,  122,  132,  147 

Billings,  147 

Binz,  362,  386 

Birt,  413 

Blanchard,  16,  70,  71,  72,  78,  399,  426, 

443 
Bleumchen,  386 
Bloch,  129 
Bloombergh,  155 
Blumer,  92 
Bodnar,  272,  281 
Boinet  and  Salabert,  268,  282 
Borius,  216,  240 
Borrel  and  Marchoux,  458 
Borrow,  387 
Botazzi,  140,  143,  147 
Botazzi  and  Pensuti,  140,  142,  143,  147 
Boudin,  81,  102,  276 
Bouzian,  121 
Bowie,  262 
Boyce,  443 

Boyce,  Ross,  and  Sherrington,  443 
Braddon,  386 
Bradford,  442 

Bradford  and  Plimmer,  251,  442 
Breinl,  435,  436,  437,  438,  444,  450 
Breinl  and    Kinghorn,    452,    453,    454, 

455.  459 
Breinl,    Kinghorn,    and    Garrett,    450, 

452,  459 
Breinl  and  Todd,  445 
Brignoni,  347,  359 
Broden,  429 
Brousse,  143 
Brown,  393 
Brown,  P.  K.,  147 
Browning,  378 

Bruce,  428,  429,  437,  438,  439,  442,  444 
Bruce  and  Nabarro,  443 
Brumpt,  429,  437 
Brumpt  and  Wurtz,  444 
Brunnhoff,  108 
Buchanan,  122,  358 
Bull,  273,  281 
Burns,  W.  B.,  263 


463 


464 


INDEX   OF    AUTHORS. 


Burot,  So,  394 
Butler,  451,  459 
Butschli,  247,  256 

Cabot,  129 

Caccini,  32,  121,  263 

Cahn,  297 

Calandrucio,  83,  116 

Calkins,  248 

Calmette,  279 

Campbell,  262 

Canalis,  ^^,  34,  53,  268,  282 

Cappogrossi,  341',  364,  387 

Carbone,  139 

Cardamantis  and  Canalis,  263,  297 

Cardamantis,  391,  394,  397,  398 

Carlisle,  459 

Carroll,  63 

Carter,  445,  455 

Casigrandi,  350,  407 

Castellani,  41  1,  426,  428,  429,  443 

Caventou,  360 

Celsus,  4,  12 

Celli,  6,  7,  12,  13,  18,  22,  34,  74,  So,  81, 
82,  83,  94,  103,  109,  112,  114, 
118,  122,  134,  138,  140,  145, 
239,   240,   245,   250,   345,   346, 

347-   349-   35°.   35*.   358,   359. 

380,  407,  408 
Celli  and  Casigrandi,  358 
Celli  and  Guarnieri,  53 
Celli  and  Sanfelice,  54 
Chamberlain,  105,  in,  178,  222 
Charvot,  282 

Chatterjee,  77,  418,  426,  443 
Chaussat,  428,  442 
Chenzinsky,  340 
Chiarini,  268,  273 
Chiarini  and  Bardellini,  268 
Childe,  427 
Christophers,   12,  41,   75,   97,   132,   147, 

359,  414,  418,  420,  421,  422, 

426,  427 
Christy,  429,  440,  443,  444,  458 
Ciarrochi,  102 
Clarke,  411 
Cochran,  296 
Coffin,  155 
Cohn,  445 
Colin,  13,  138,  222 
Colosanti,  142,  147 
Columella,  4,  7,  12,  56 
Cook,  458 
Coronado,  92,  103 
Corre,  391 

Councilman,  6,  12,  32,  53,  148,  160 
Craig,  C.  F.,  12,  18,  55,    103,    122,    160, 

166,   263,   283,   297,   340,  341, 

359.  387 
Crawley,  60 
Crespin,  341 
Cropper,  458 
Crosse,  407 
Cuboni,  6 
Cummings,  391 
Curry,  285,  341 


Da  Costa,  285,  297 

Daniels,  70,  75,  77,  263,  2S3,  341,  394, 

395.  397.  407,  408 
Danilewsky,   14 
Darling,  460,  461 
Davidson,  82,  114,  283,  394,  407 
Deaderick,  404,  40S 
De  Brun,  262 
De  Rossi,  273,  274 
Di  Mattei,   84,    102,  103,  116,  122,  358, 

380 
Dionisi,  115,  130,  131,  146,  164,  357 
Dionisi  and  Bignami,   164 
Dock,  ft,  34,  54,  134,  147,  14S,  160,  292, 

297.  337-  372 
Doenng,  393 
Doflein,  251,  442 
Donne,  73 

Donovan,  412,  413,  420,  422,  425,  426 
Dubini,  268 
Duchek,  121,  122 
Duden,  240 
Duncan,  344 
Durham,  383 
Dutrouleau,  391,  407 
Dutton,    97,    114,    359,    428,   429,    441, 

443.  44  5 
Dutton  and  Todd,  428,  429,  441,  442, 

443.  444,   448,   449.   451.   455. 
456,  458,  459 
Dutton,  Todd,  and  Christy,  443 

Edmonds,  282 

Ehrlich,  100,  260,  261,  378,  380,  386 

Elting,  7,  83,  116,  122 

Elliot,  97,  1 14 

Elmassion,  428,  442 

Englemann,  247 

Ewing,  J.,   55,   129,   148,   160,  245,  263, 

285,  297,  340 
Evans,  428,  442 

Fassina,  272,  282 

Favre,  78 

Fayrer,  13,  281 

Feletti,  6,  35,  53 

Felkin,  122 

Felt,  78 

Ferreri,  273,  274 

Feuchtwanger,  374,  386 

Finot,  175 

Fischer,  274,  358 

Fish,  129 

Flexner,  S.,  144,  153 

Flournoy,  445 

Fliigge,  56 

Ford,  J.,  385,  387 

Forde,  429,  443 

Fraenkel,  447,  450 

Francis,  145 

Frank,  273 

Frerichs,  5,  138 

Freund,  141 

Frosch,  344,  359 

Fuellborn  and  Meyer,  452,  459 


INDEX    OF    AUTHORS. 


465 


Gabritchewsky,  458 

Galli-Valerio,  78,  351,  359 

Gancel,  297 

Garrett,  450 

Gautier,  55,  383,  387 

Gee,  141 

Gerhardt,  7,  83,  102,  116 

Giemsa,  317,  340,  423 

Giles,  63,  69,  71,  78,  411,  425 

Glogner,  147,  263,  268 

Gluge,  428 

Goeldi,  70 

Golgi,  6,  13,  19,  26,  32,  35,  53,  134,  135. 

144,  147,  362,  363,  364,  368,  386 
Gorgas,  348,  352,  358,  393 
Gosio,  344,  359 
Gowers,  268 
Grabham,  70 
Graham,  63,  70,  355 
Grassi,  6,  7,  8,  12,  13,  18,  55,  58,  59,  77, 

86,  88,  91,  105,  117,  122,  358, 

383,  386 
Grassi,    Bignami,   and    Bastianelli,    77, 

135  ,       • 
Grassi  and  Feletti,  3  5,  53 

Grawisz,  129 

Gray,  429,  435,  436,  437,  438,  44i-  443. 

444 
Gray,  St.  George,  380,  386 
Gray  and  Tulloch,  429,  435,  444 
Greig,  429,  437,  438,  441,  443,  444 
Greig  and  Gray,  441,  443,  444 
Griesinger,  175,  281 
Grixoni,  341 
Grocco,  282 
Groff,  4 
Gros,  386,  428 
Grube,  428,  430 
Gualdi,  83,  145,  370,  387 
Gualdi  and  Antolisei,  83,   102,  116 
Guarnieri,  22,  148,  160,  273,  380 
Guttman,  380,  386 

Haendel,  446,  452 

Haig,  39s 

Hamburger,  92 

Harris,  340 

Haspel,  222 

Hertwig,  2  50 

Hertz,  277,  282 

Herz,  270 

Hewettson,  12,  34,  113,  142,  171,  175 

Hirsch,  113 

Hirshberg,  75 

Hippocrates,  4,  12 

Horcicka,  142,  147 

Hope,  97 

Hotz,  274 

Hovorka,  385,  387 

Howard,  68,  78,  348 

Huchard,  269 

Hunt,  341 

Iacoangelini,  142,  147 
Ipscher,  394 
Ivanoff,  380,  386 

3° 


Jackson,  32,  118,  122,  178 

Jacobi,  273,  281 

James,  32,  97,  233,  263,  349,  359,  414, 

420,  422,  427 
Jancso,  78,  109,   1  1  7 
Jilek,  358 
Jourdan,  268 

Kahler  and  Pick,  268,  281 
Karlinsky,  447,  458 
Kelsch,  129,  130,  132,  138,  146,  160 
Kelsch  and   Kiener,   12,   190,   262,   270, 

280,  281,  282,  408 
Kempner,  443 
Kent,  442 

Kieweit  de  Jonge,  142,  147,  351,  359 
King,  F.  A.,  7,  56,  387 
Kmghorn,  450,  452,  453,  454,  455 
Kinyoun,  285,  297 
Kipp,  262,  273,  282 
Klebs,  5,  13 
Kleine,  386 
Klemperer,  341 

Knapp,  445,  446,  448,  450,  452,  454 
Koch,  8,  56,  57,  60,  77,  93,  96,  97,  98, 

102,    103,    114,    115,    175,   233, 

263,   343.   357-   358,   375.   391. 

398,  435.  445.  447-  455.  459 
Kolosvary,  387 
Kronecker,  341 
Kruse,  15,  54,  429 
Kuchel,  407 
Kuhn,  357,  385,  387 
Kunst,  380,  386,  387 

Labbe,  15,  54 

Laborde,  343,  358 

Lagrand,  394 

Lamb,  453 

La  Monaco,  74,  322,  341,  363 

La  Monaco  and  Panichi,  322,  341,  363, 
386 

Lancereaux,  269,  278,  282 

Lancisi,  5,  7,  13,  269 

Landouzy,  221 

Lankester,  428 

Laveran,  6,  12,  13,  14,  54,  55,  56,  83, 
122,  134,  138,  144,  148,  175. 
190,  216,  221,  222,  223,  262, 
270,  272,  285,  340,  341,  343. 
358,  362,  408,  413,  420,  422", 
425,  426,   429,  430,  438,  442, 

444 
Laveran   and   Mesnil,    430,    431,    432, 

436,  440 
Laveran,  Mesnil,  and  Nabarro,  440,  444 
Lazear,  55,  63 
Lebert,  445,  446 
Leboeuf,  444 
Ledingham,  420 
Leishman,  315,  340,  411,  412,  413,  416, 

418,  420,  421,  424,  425,  427, 

448 
Leishman  and  Statham,  427 
Lemoine,  143 
Leukowicz,  386 


466 


INDEX    OF    AUTHORS. 


Levick,  296 

Levrier,  273,  281 

Lewis,  42S 

Leyden,  V.,  240 

Liel,  274 

Linton,  429,  437,  444 

Liston,  71,  73 

Litter,  129 

Livingstone,  448 

Loeff,  Van  der,  407 

Loew,  72,  73 

Low,  89,  354,  41' 5,  425,  443,  458 

Low  and  Mott,  443 

Ludlow,  C.  S.,  70,  74 

Liihe,  16,  55,  434 

Lutz,  70 

Lynch  and  Scott,  394 

Lyons,  285,  297,  427 

MacCallum,  7,  55,  57,  77 

Mackie,  446,  450,  451,  452,  453,  454, 

455.  456,  459 

MacNamara,  282 

MacNeal,  436,  443 

Magnin,  272,  282 

Maillot,  175,  262 

Mannaberg,  6,  12,  15,  32,  34,  54,  116, 
122,  130,  142,  145,  171,  175, 
190,  215,  217,  240,  260,  267, 
269,  279,  283,  363,  366,  391, 
395.  396,  408 

Manson,  P.  Thorburn,  90 

Manson,  Sir  P.,  7,  32,  49,  55,  56,  57,  63, 
77.  83.  86,  9°.  I°3>  IJ5,  JI7. 
269,  340,  341,  344,  361,  372. 
38°.  391.  394,  395,  397,  399, 
407,  408,  411,  412,  414,  415, 
420,  425,  427,  429,  431,  443, 

444,  445,  447,  459 

Manson  and  Low,  414 

Marchand,  412,  420 

Marchiafava,  6,  7,  12,  13,  14,  17,  32,  83, 
86,  92,  106,  134,  135,  138,  144, 
150,   220,   221,   223,   261,   277, 

278,  379 
Marchiafava  and  Bignami,   54,  80,  84, 
94,    117,    118,    122,    128,    130, 
148,   151,   170,   182,   184,   203, 
214,   253,   259,   267,   271,   282, 

363,  369,  376,  38o>  391,  407 
Marchiafava  and  Celli,  14,  32,   53,   134, 

138 
Marchoux,  57,  120,  262,  407,  429,  458 
Mariani,  387 
Marino,  316 
Mariotti,  7,  83 
Mariotti  and  Ciarrochi,  102 
Mariotti-Bianchi,    122,    240,    242,   244, 

245,  263 
Markham,  360 
Martin,  95,  272,  282 
Martin  and  Leboeuf,  444 
Martirano,  370,  387 
Massey,  458 
Masucci,  387 
Mathis,  263 


Maupas,  250 

Maurel,  94,  279,  282 

Maurer,  42,  55,  375 

Maximow,  128 

Maxwell- Adams,  429 

Meckel,  5,  13,  138,  146 

Megnin,  458 

Meigs,  138 

Mense,  356,  358 

Meigen,  71,  73 

Mericourt  de,  391 

Mesnil,  413,  422,  425,  426 

Metchnikoff,    14,    100,    134,    135,    137, 

260,  453 
Metin,  282 
Meyer,  452 
Milne,  448,  455 
Mmchin,  416,  431,  435,  459 
Minchin,  Gray,  and  Tulloch,  435,  444 
Mitchell,  5,  13,  92 
Moffatt,  404 
Mole,  444 

Monti,  148,  150,  160 
Moore,  283 
Morehead,  281 
Mori,  380,  407 
Morton,  5,  13 
Moscato,  393 
Mosse,  262 

Mott,  439,  441,  443,  444 
Muehleck,  281,  297 
Midler,  O.  F.,  247 
McCrae,  459 
McFarland,  426 
McLean,  270 

Nabarro,  428,  429,  438,  439,  440,  441, 

444 
Navarre,  118 
Nazari,  277 
Neave,  426 
Neveu-Lemaire,  12 
Nicolle,  411,  413,  424 
Nikastro,  380 
Nocht,  315,  340,  434 
Norris,  445,  450 
Norris,    Pappenheimer,    and   Flournoy, 

4  59 
Nott,  7,  56 
Novi,  380 

Novy,  424,  425,  435,  444,  450 
Novy  and  Knapp,  445,  446,  447,  448, 

45°,  451-  452,  453-  454,  459 
Novy  and  MacNeal,  436,  443,  458 
Nuastro,  387 
Nuttall,  66,  77,  85 

Obermeieri,  445,  458 
Oliver,  313 
Ollwig,  344,  359 

Osier,  6,   13,   14,  27,   53,   134,  221,  262, 
285,  296,  297,  298,  360 

Palladius,  4,  13 
Pampoukis,  394 
Panichi,  116,  322,  341,  363,  386 


INDEX    OF    AUTHORS. 


467 


Panse,  98,  103 

Pappenheimer,  445 

Parker,  145 

Pasminik,  262,  269,  282 

Patton,  413,  418,  419,  420,  422,  423,  427 

Pelletier,  360 

Pennoff,  273 

Pensuti,  140,  143,  147,  270 

Pepper,  129 

Peters,  123 

Petit  and  Verneuil,  282 

Pfeiffer,  56,  407 

Phillips,  426 

Pianese,  411,  413,  424 

Pick,  268,  281 

Plehn,  A.,  34,  74,  78,  95,  roo,  103,  129, 
147,  190,  216,  262,  263,  316, 
340,  343.  344.  358,  386,  394, 
395,  403,  404,  406,  408 

Plehn,  F.,  188,  358,  379,  380,  395,  407 

Plimmer,  251,  442,  444 

Poch,  132 

Politzer,  273 

Poncet,  273,  281 

Powell,  341,  458 

Pressat,  348 

Procaccini,  355,  358 

Prowazek,  251,  432,  434,  445,  447,  459 

Pucci,  380 


Quennec,  406 
Queriolo,  144 


Rabinowitsch,  443 

Rabinowitsch  and  Kempner,  443 

Range,  262 

Rasch,  374,  386 

Raymond,  268 

Raynaud,  282 

Reed,  W,  63,  144,  153,  285 

Rem-Picci,  140,  141,  142,   147,  262,  270 

Rho,  13,  297,  399 

Richard,  6,  13,  144,  358 

Richard,  C,  224 

Ritchie,  394,  397 

Rogers,  L.,  49,  93,  132,  133,  147,  341, 
411,  413,  415,  416,  418,  419, 
420,  422,  423,  425,  426,  427, 

444 
Romanowsky,    22,    54,    128,    312,    314, 

34°,  363,  366,  414 
Roque,  143 
Rose,  386 
Rosenau,  145 
Rosenbach,  92,  103 
Rosenstein,  141,  270,  282 
Ross,  P.,  448,  455,  456,  459 
Ross,  R.,  7,  13,  18,  57,  77,  83,  86,  352, 

354,  358,  359,  4ii,  413,  4i6, 

424,  425 
Ross  and  Milne,  448,  455,  458 
Rossoni,  134,  146,  407 
Rouget,  428,  442 
Rowley,  55 


Ruata,  426 

Ruge,  41,  42,  54,  ss 


Sacchi,  268,  282 

Sacharoff,  7,  13,  18,  54,  83,  84,  92,  102, 

103 
Salabert,  268 
Salisbury,  5,  13 
Salvin-Moore,  435 
Sambon,  89,  90,  354,  399,  431,  443,  444, 

445,  446 
Sanfelice,  34,  54 
Sarda,  274 
Sbacchi,  354,  359 
Schaudinn,  F.,    16,    19,  41,  42,  46,    55, 

59,   78,  92,  121,  245,  249,  263, 

357,  359,  383,  384,  387,  446, 

447,  448,  458,  459 
Schaudinn  and  Hoffman,  458 
Schellach,  446,  447,  448,  449 
Schellong,  12,  282 
Scheube,  113,  222,  224 
Schewiakoff,  60 
Schilling,  240,  263,  459 
Schmidt,  279,  282 
Schoo,  358,  370 
Schiiff  er,  375 
Schuffner,  26,  55,  78,  128 
Schwalbe  and  Solley,  129 
Scott,  394 
Seal,  393 
Sedan,  273 
Seely,  273,  282 
Segard,  269,  282 
Senator,  282 
Sereni,  121,  123 
Sergent,  74,  78,  359 
Shakespeare,  285 
Sherrington,  443 
Shipley,  66 
Simms,  394 
Smith,  J.  B.,  78 
Solley,  129 
Sorel,  262 
Spadoni,  80 
Spiller,  262 
Stassano,  251 

Statham,  418,  420,  426,  427 
Steel,  442 

Stengel,  White,  and  Pepper,  129 
Stephens,  12,  41,  97,  354,  359,  395, 

444 
Stephens  and  Christophers,  41,  75 

103,   114,   132,   !47,   233, 

322,  34i,  359,  391,  396, 

444,  4  59 
Sternberg,   G.   M.,   6,   13 

280 
Stilling,  273 
Strachan,  103 
Strasser  and  Wolf,  263 
Studel,  407 
Sulzer,  273,  282 
Sydenham,  5,  13 
Sylvaine,  380,  387 


54,   11 


4°7. 

.  97, 
263, 
408, 


8,   221, 


468 


INDEX    OF    AUTHORS. 


95.  Io: 


Thayer,  W.  S.,  12,  34,  55,  77,  103,  106, 
109,  i2i,  122,  123,  134,  140, 
144,    148,    160,    171,   22i,   262, 

27I,     278,     282,     296,     2Q1,     380, 
407 

Thayer  and   Hewettson,    12,    113,    142, 

171,  175,  252 
Theiler,  428,  442 
Theobald,  63,  65,  69,  70,  78 
Thomas,  429,  436,  437,  438 
Thomas  and  Breinl,  429,  437,  444 
Thomas  and  Linton,  429,  437,  444 
Thompson,  285,  297 
Tictin,  453.  454 
Todd,  429,  441,  442,  443,  444,  440,  451, 

4  55.  4  56 
Tomaselli,  398,  407 
Tomassi-Crudelli,  5,  13,  8i 
Torti,  5,  13,  268 
Torti  and  Angelini,  282 
Travers,  348 

Tsuzuki,  73,  283,  353,  359 
Tuffier,  440 

Tulloch,  429,  435,  436,  437,  438,  444 
Turk,  130 

Uhlenhuth,  446 

Uhlenhuth  and  Haendel,  416,  452,  450 

Vagedes,  344,  359 

Valentin,  428 

Vallin,  282 

Varro,  4,  7,  12,  56 

Vaughn,  V.,  285 

Veratas,  398 

Verneuil,  282 

Vincent,  80,  268,  285,  297,  406 


Virchow,  5,  13,  138,  146 
Vitruvius,  56 
Voges,  442 

Ward,  H.   B.,  444,  440 

Warrington,  443 

Watson,  348 

Weatherfey,  280 

Welch,  W.  H.,  144,  153 

Wellman,  438,  444,  458 

Werlhof,  240 

White,  129 

Whitmore,  74 

Winslow,  122 

Winterbottom,  429,  443 

Witherington,  285 

Woldert,  77 

Wolf,  263 

Wolff,  273 

Woodcock,  43  1 

Woodward,  284,  292,  296,  297 

Wright,   J.   H.,    22,    60,   313,   340,   366, 

411,  413.  423,  424,  425 
Wurtz,  437,  444 

Yanarris,  276 
Yarr,  262 
Young,  297 

Zeri,  83,  147 

Zettnow,  449,  450,  459 

Zieman,  12,  16,  54,  55,  74,  77,  78,  118, 

121,     122,     123,     I32,     I42,     I44, 
147.     17  5.     240,     242,     245,     263, 

340,   343.   344,   359,   363,   3^6, 
386>  434 


GENERAL  INDEX 


Abdomen,   symptoms  connected  with, 

279 
Abortion,  as  complication,  280 
Adrenal  glands,  pathology  of,  152 
Aestivo-autumnal  malaria,  176 

classification  of  parasites  of,  15,31 

frequency  of  occurrence  of,  176 

parasites  of,  31,  39,  50 

prodromal  symptoms  of,  180 

prognosis  of,  299,  300 

recurrences  in,  240 

red  corpuscles  in,  39,  191 

remittent  forms  of,  224 

sub-continued  forms  of,  2  53 

symptoms  of,  180 

temperature  curve  in,  180 

typhoid  and,  292 

varieties  of,  15,  180 
Age  as  predisposing  cause,  114 
Agglutination  test,  322 
Air,  transmission  by,  79 
Albuminuria,  as  sequel  of,  270 

complication  of,  278 
Algid  malaria,  221 
Altitude,  as  predisposing  cause,  105 
Amaurosis,  as  a  sequela,  273 
Amoebae,  occurrence  of,  279 
Anaemia,  malarial,  129,  274 

in  cachexia,  2  58 

recovery  from,  302 

red  corpuscles,  in,  130 

post-malarial,  274 

prognosis  of,  302 

varieties  of,  131 
Anophelinae,  63 
Anchylostoma  duodenale,  occurrence  of, 

281 
Aphasia,  267 
Apoplexy,  symptoms  suggesting,  218 

differential  diagnosis  of,  332 
Appendicitis,  symptoms  of,  190 

differential  diagnosis  of,  332 
Aristochin,  380 
Arteritis  as  sequela,  269 

Bacillus  malarias,  5 

Bacteria  in  malaria,  5 

Band  forms  of  parasites,  30 

Bilious  remittent  fever,  224 

Blood,  examination  of,  191,  308 
artefacts  in,  128,  309,  318 
changes  in  red  corpuscles,   25,  31, 
39.  127 


Blood,  citrated  cultures  of,  93 

examination  of,   in  pernicious  in- 
fections, 220 
general  pathology  of,  127 
haemoglobin  of,  128,  133 
in  aestivo-autumnal  infections,  39, 

191 
in  malarial  cachexia,  274 
inoculation  of,  83,  115 
in  quartan  infections,  31,  191 
in  tertian  infections,  25,  191 
leucocytes  in,  127,  132,  322 
segmenting  forms   in,    21,    24,    28, 

37>  39 
staining  of,  128,  312 
summary  of  changes  in,   140 

Bone-marrow,  changes  in,  156 

Brain,  pathology  of,  148 
blood-vessels  of,  148 
changes  in  nerve  cells  of,  149 
endothelial  cells  in,  149 
free  pigment  in,  149 
free  plasmodia  in,  148 
macrophages  in,  149 
pigmented  leucocytes  in,  149 
segmentation  of  plasmodia  in,  148 

Bronchiectasis,  277 

Bronchitis,     acute,     as     complication, 
189,  276 

Cachexia,  discussion  of,  256 

pathology  of,  164 

prognosis  of,  302 

symptoms  of,  258 

treatment  of,  382 
Cadaver,  appearance  of,  148 
Cardiac  weakness,  221 

treatment  of,  381 
Cardialgic  form,  222 
Chagres  fever,  10 
Children,  malaria  in,  192 

frequency  of,  in,  192 

symptoms  in,  192 
Chills,  172 

analysis  of  character  of,  186 

in  aestivo-autumnal  malaria.  180 

in  quartan  malaria,  176 

in  tertian  malaria,  172 
Chinchonidin,  370 
Chinchonin,  370 
Cholera  as  a  complication,  280 

differential  diagnosis  from,  339 
Choleraic  form  of  malaria,  221 


469 


47° 


GENERAL    LNDEX. 


Chorea,  occurrence  of,  268 
Chromatin,  staining  reactions  of ,  23,  30, 

39 
Circulatory  system,  sequela?  in,  269 

complications  in,  278 
Classification  of  plasmodia,  14 

biological,  14 

Blanchard's,  16 

clinical,  169 

Craig's,  17 

Grassi  and  Feletti's,  15 

Kruse's,  1  5 

Labbe's,  1  5 

Luhe's,  16 

Mannaberg's,  1  5 

Sacharoff 's,  1  5 

Schaudinn's,  16 

Thayer  and  Hewettson's,  15 

Zieman's,  16 
Climate,  influence  of,  85,  104 
Collapse,  treatment  of,  381 
Congenital  malaria,  120 
Conjugation,  intracorpuscular,  244 

effect  of  quinine  on,  370 

morphology  of,  246 

relation  to  latency  and  recurrences, 
248 

significance  of,  247 

spontaneous  recovery  and,  261 
Constipation,  occurrence  of,  189 
Convalescence,  treatment  of,  381 
Coma,  occurrence  of,  218 
Comatose  pernicious  malaria,  218 
Complications,  276 

abortion  as,  280 

acute  specific  diseases  as,  280 

animal  parasites  as,  281 

in  circulatory  system,  278 

in  gastro-intestinal  system,  279 

in  genito-urinary  system,  278 

in  nervous  system,  276 

in  respiratory  system,  276 

insolation  as,  280 
Corpuscles,  red  blood-,  25 

artefacts  in,  31,  39,  128,  309,  318 

changes  in,  25,  31,  39 

haemoglobin  in,  25,  31,  39 

morphology  of,  25,31 

plasmodia  in,  number  of,  36,  38 

reduction  of,  131,  274 
Corpuscles,  white,  reduction  in,  127 
Country,  malarial,  85 
Crenations  of  red  corpuscle,  36,  309 
Crescents,  development  of,  in  man,  49 

development  of,  in  mosquito,  56 

discovery  of,  6,  32 

distinction  of  tertian  and  quotid- 
ian, 48 

fertilization  of,  49 

proportion  of  cases  showing,  49 
Culicidae,  62 
Cultivation  of  plasmodia,  92 

Deafness  from  quinine,  378 

as  a  sequela,  273 
Delirium  as  a  symptom,  191 


Dengue,  leucocytes  in,  131 

differential  diagnosis  of,  335 
Diagnosis  of  quotidian  form,  331 

of  tertian  form,   331 

of  pernicious  forms,  331 

by  clinical  methods,  330 

by  laboratory  methods,  307 
Diagnosis,  differential,  332 

from  acute  specific  diseases,  335 

from  apoplexy,  339 

from  cholera,  339 

from  dysentery,  337 

from  endocarditis,  337 

from  hepatic  abscess,  337 

from  infections    with    other    para- 
sites, 319,  335 

from  insolation,  339 

from  leukaemia,  339 

from  purpura,  339 

from  tuberculosis,  335 

from  typhoid  fever,  332 

from  yellow  fever,  333 
Diagnosis  of  malarial  mosquitoes,  323 
Diarrhoea,  occurrence  of,  189 
Diazo  reaction,  occurrence  of,  142 
Digestive  system,  complications  in,  279 

sequela?  in,  269 
Diphtheria,  occurrence  of,  280 
Dissection  of  mosquitoes,  325 
Distribution,  geographical,  8 

factors  influencing,  9 

in  Africa,  1 1 

in  Asia,  1 1 

in  Central  America,  10 

in  Europe,  10 

in  North  America,  9 

in  South  America,  10 

in  West  Indies,  10 
Diabetes  mellitus,  occurrence  of,  281 
Diet  in  acute  fever,  381 

in  convalescence,  381 
Digestive  system,  complications  in,  279 

sequelae  in,  269 
Dysentery,  occurrence  of,  270,  279 

differential  diagnosis  of,  337 
Dysenteric  malaria,  222 

Ear,  sequelae  affecting,  273 
Elevation  and  malaria,  105 
Endemic  malaria,  8 
Entamoeba    histolytica,     occurrence    of 

279,  281 
Endocarditis,  as  a  complication,  278 

as  a  sequela,  269 

differential  diagnosis  of,  337 
Enteritis,  acute,  as  a  symptom,  269 

chronic,  ulcerative,  269 
Epidemic  malaria,  9 
Epididymitis,  malarial,  272,  279 
Epigastrium,  pain  in,  190 
Epistaxis,  occurrence  of,  254 

in  malarial  cachexia,  258 
Erysipelas,  occurrence  of,  280 
Erythrocytes,   changes  in,    25,   31,   39, 

I27>  3°9.  3l8 
Esanophele,  383 


GENERAL    INDEX. 


471 


Etiology,  3 

Euchinin,  380 

Eye,  sequelae  affecting,  273 


Facial  appearance,  188 
Fever,  etiology  of,  144 

cause  of  pernicious,  216 

causes  of  variation  in,  184 

continuous,  252 

crisis  of,  182 

diagnostic  features  of,  330 

effect  of  quinine  on,  184 

in  children,  192 

incubation  of,  115 

latent,  161,  228 

masked,  235 

modifications  of,  184 

pseudocrisis  of,  182 

quartan,  176 

puerperal,  280 

remittent,  224 

sub-continued,  253 

tertian,  172 

tertian  aestivo-autumnal,  180 

typho-malarial,  284 

variations  in,  184 

Malta,  280 

long-interval  fevers,  171 

recurrences  of,  240 
Filipinos,  malaria  in,  11,  283 

filariasis  in,  281 
'  Flagellate  forms,  activity  of,  43,  48 

active  form  of,  42 

degenera  ion  of,  44 

development  of,  43 

discovery  of,  6 

methods  of  obtaining,  318 
of  staining,  318 

origin  of,  42,  44 

passive  form  of,  43 

pigment  in,  43,  48 

sexual  nature  of,  18,  42 

significance  of,  7,  18,  42 

staining  reactions  of,  46,  48 

varieties  of,  42,  48 


Gall-bladder,  pathology  of,  152 

Gametes,  nature  of,  40 

differentiation  of,  41,  48 

of  quartan  plasmodium,  48 

of  tertian  plasmodium,  43,  45 

of  the  aestivo-autumnal  plasmodia, 

.    48 
Micro-,  43,  44,  46,  48,  51 
Macro-,  43,  46,  48,  50,  52 
development  in  man,  43 

in  mosquito,  56 
relation  to  mosquito  of,  42 
staining  reactions  of,  45,  52 
Gangrene,  occurrence  of,  274,  279 
Gastralgia,  occurrence  of,  222 
Gastro-intestinal    tract,    complications 
in,  279 
sequelas  in,  269 


Genito-urinary    system,    complications 
in,  278 

sequelae  in,  270 
Glands,  lymphatic,  in  malaria,  272 

in  kala-azar,  272 

in  sleeping-sickness,  272 

in  spirochetosis,  272 

in  trypanosomiasis,  272 
Glandular  system,  sequelae  in,  271 
Glycosuria,  occurrence  of,  2  7  1 

Hcemato phylum  malarice,  14 
Hcemamceba  prcecox,  16 
quartance,  16 
tertiance,,  16 
Halteridium,  7 
Haemoglobinuric  fever,  391 
blood  in,  400 

complications  and  sequelae  of,  403 
definition  of,  391 
diagnosis  of,  403 
epidemics  of,  393 
frequency  of,  393 
geographical  distribution  of,  391 
history  of,  391 
incubation  of,  401 
malarial  theory  of,  395 
pathology  of,  399 
predisposing  causes  of,  394 
prognosis  of,  403 
prophylaxis  of,  403 
quinine  in,  404 

theory  of,  398 
race  and,  395 
recurrences  of,  395 
residence  and,  394 
seasonal  prevalence  of,  393 
specific  theory  of,  399 
symptoms  of,  401 
treatment  of,  404 
urine  in,  401 
Haemoglobin,  reduction  of,  133 

retraction  of,  128,  309 
Haemorrhage,  occurrence  of,  223,  280 
from  the  bowels,  223 
in  malarial  cachexia,  258 
in  pernicious  malaria,  223 
Haemosiderin,  origin,  139 

character  of,  139 
Headache,  in  tertian  fever,  191 

in  aestivo-autumnal  fever,  191 
in  quartan  fever,  191 
Heart,  pathology  of,  151 
sounds  of,  171,  184 
symptoms  connected  with,  269 
Hemiplegia,    occurrence    of,    220,    267, 

276 
Hepatitis,  occurrence  of,  190 
Herpes,  occurrence  of,  188 
History  of  malaria,  3 

periods  of,  4 
Hyalin  stage  of  plasmodium,  20,  27,  35, 

36 
in  aestivo-autumnal  fever,  35,  37 
in  quartan  fever,  27,  30 
in  tertian  fever,  20,  23 


472 


GENERAL    INDEX. 


Hyalin  stage  of  Plasmodium,  number 
in  infected  cell,  36,  38 
staining  reactions  of,  23,  30,  39 

Hysteria,  occurrence  of,  276 

Histo plasma  capsulatum,  400 

Immunity,  natural,  93 

absolute,  acquired,  95 
natural,  04 
relative,  94 

acquired,  95 

cause  of,  in  malaria,  101 

congenital,  94 

natives  and,  95 

racial,  95 

relative,  acquired,  95 

theories  of,  100 

various  forms  of  malaria  and,  102 
Incubation,  period  of,  1 1  5 

after  inoculation  by  the  mosquito, 

117 
after  inoculation  of  malarial  blood, 

XI5 
after  natural  infection,  117 

cause  of  prolonged  periods  of,  120 

prolonged  periods  of,  1  iq 
Insanity,  occurrence  of,  269 
Iritis,  occurrence  of,  273 
Infection,  latent  malarial,  228 

by  air,  79 

by  inoculation,  83 

by  mosquitoes,  84 

by  water,  81 

by  winds,  81,  108 

chronic,  256 

combined,  284 

family,  233 

in  adults,  233 

in  children,  192,  233 

masked,  235 

mixed,  2  56 
Inoculation,  direct  infection  by,  83 

experiments  in,  83,  118 

experimental  transmission  by  the 
mosquito,  84 

by  malarial  blood,  83 
Insomnia,  occurrence  of,  269 
Insolation,  occurrence  of,  280 

differential  diagnosis  of,  339 
Intestines,  pathology  of,  151 

necrosis  of,  152 

Plasmodia  in,  152 

ulceration  of,  1  52 

Jaundice,  occurrence  of,  224,  253,  335 

Kala-azar,  cause  of,  411 

differential  diagnosis  of,  335 
leucocytes  in,  131 

Keratitis,  occurrence  of,  273 

Kerosene  as  a  prophylactic,  349 

Kidneys,  tubules  of,  1  56 

general  pathology  of,  155 

Latent  malaria,  161,  228 
as  a  complication,  230 


Latent  malaria,  duration  of,  239 
etiology  of,  244 
frequency  of,  229 
pathology  of,  161 
Plasmodia  in,  161,  228 
types  of  infection  in,  22S 
Laverania  malaria,  15,  16 
Leishmania-donovani ,  41 1 

blood  in  infection  with,  422 
biological  position  of,  412 
cultivation  of,  418 
demonstration  of,  423 
distribution  in  man  of,  420 
elimination  of,  423 
geographical  distribution  of,  412 
history  of,  411 
morphology  of,  413 

in  cultures,  415 
multiplication  of,  417 
occurrence  in  blood  of,  422 
pathogenicity  of,  420 
transmission  of,  419 
Leishmania   tropicum  and   Leishmania 

infantum,,  424 
Leucocytes,  reduction  of,  131 

diagnostic  value  of  pigmented,  32  1 
differential  count  of,  132 
Leucocytosis  in  malaria,  131 
Leukaemia,  differential  diagnosis  of,  339 
Locality,  relation  of,  to  predisposition, 
104 
in  prognosis,  298 
Lungs,  pathology  of,  1  50 

broncho-pneumonia  of,  151 
capillaries  of,  151 
free  pigment  in,  151 
phagocytes  in,  151 
Plasmodia  in,  151 
Liver,  pathology  of,  152 
capillaries  in,  1  53 
cirrhosis  of,  153,  271 
epithelium  of,  1  53 
focal  necrosis  in,  1  53 
free  pigment  in,  1  53 
Kupfer's  cells  in,  153 
macrophages  in,  1  53 
phagocytes  in,  153 
Plasmodia  in,  153 

Macrogametes,  41,  43,  46,  48 
Macrophages,  1  54 
Malta  fever,  280 

differential  diagnosis  of,  335 
Mania,  occurrence  of,  269,  276 
Marshall's  dots,  40 
Masked  malaria,  235 

duration  of,  239 
Merozoites,  of  tertian  malaria,  21,  24 

of  aestivo-autumnal  tertian,  39 

of  quotidian,  37 

of  quartan  malaria,  28,  30 
Melancholia,  occurrence  of,  269 
Melanaemia,  occurrence  of,  5,  137 

of  adrenal  glands,  152 

of  brain,  149 

of  heart,  151 


GENERAL    INDEX. 


473 


Melanaemia,  of  kidneys,  155 

of  liver,  153 

of  lungs,  151 

of  retina,  1  50 

of  spleen,  1 54 

of  stomach  and  intestines,  152 
Melanin,  origin  of,  138 

chemistry  of,  139 

distribution  of,  139 
Measles,  occurrence  of,  280 
Memory,  loss  of,  267 
Meningitis,  occurrence  of,  276 
Mental  sequelae,  267 

prognosis  of,  302 
Methylene  blue  as  remedy,  380 
Microgametocytes,  41 

of  aestivo-autunal  tertian,  51 

of  quotidian,   51 

of  quartan  malaria,  48 

of  tertian  malaria,  43,  46 
Micro  gametes,  41 

of  aestivo-autumnal  tertian,  51 

of  quotidian,   51 

of  quartan  malaria,  48 

of  tertian  malaria,  44,  47 
Micro-organisms,  and  malaria,  5 
Mosquitoes,  63,  86 

classification  of,  70 

collection  of,  324 

destruction  of,  347 

development    of  plasmodia  in,  56, 
86 

diagnosis  of  malarial,  323 

dissection  of,  325 

distribution  of,  72 

experimental  infection  by,  84 

feeding  of,  68,  323 

flying  distance  of,  69 

habits  of,  68 

hibernation  of,  69 

larvae  of,  66 

malarial,    73,  323 

mounting  of,  325 

ova  of,  66 

percentage  of  infected,  74 

period  of  incubation  in,  117 

protection  from,  89 

pupae  of,  68 

rearing  of,  328 

sectioning  of,  327 

species  of,  73,  76 

structure  of,  63 

Natives,  immunity  in,  233 

examination  of  blood  in,  232 

latent  infection  in,  232 
Nausea,  as  symptom,  189 
Necator  americanus,  281 
Necrosis,  focal,  of  liver,  1  53 

of  spleen,  155 
Nephritis,  as  a  symptom,  278 

as  a  sequela,  270 
Nervous  system,  complications  in,  276 

sequelae  in,  267 
Neuralgia,  occurrence  of,  268 
Neurasthenia,  occurrence  of,  269 


Neuritis,  multiple,  as  a  sequela,  268 
Neuroses,  occurrence  of,  276 

Occupation,  in  predisposition,  86,   114 

in  prognosis,  299 
Oocyst,  description  of,  58 
Ookinete,  description  of,   58 
Orchitis,  occurrence  of,  272,  279 
Oscillaria  malaria,  14 
Otalgia,  occurrence  of,  273 
Otitis  media,  occurrence  of,  274 

Paralysis,  bulbar,  220,  268 

occurrence  of,  220 
Paragonimus  westermanii,  281 
Paraplegia,  occurrence  of,  221,  267,  276 
Parasites,  malarial,  see  Plasmodia. 
Parotitis,  occurrence  of,  269,  281 
Paroxysms,  malarial,  171 

in  aestivo-autumnal  tertian,  180 

in  quotidian,  182 

in  quartan  malaria,  171 

in  tertian  malaria,  171 
Pathology  of  malaria,  127,  148 

general,  127 

of  fever,  144 

of  kala-azar,  420 

of  latent  malaria,  161 

of  malarial  cachexia,  164 

of  spirochaetosis,  451 

of  trypanosomiasis,  437 

special,  148 
Pernicious  malaria,  215 

classification  of,  218 

definition  of,  215 

diagnosis  of,  331 

etiology  of,  216 

frequency  of,  216 

parasites  concerned  in,  215 

prognosis  of,  300 

treatment  of,  382 
Pernicious  malaria,  forms  of,  215 

algid  form,  221 

amaurotic  form,  220 

ataxic  form,  220 

bilious  form,  224 

bulbar  form,  220 

cardialgic  form,  222 

choleraic  form,  221 

comatose  form,  218 

delirious  form,  220 

diaphoretic  form,  226 

dysenteric  form,  222 

eclamptic  form,  220 

exanthematous  form,  226 

gastralgic  form,  222 

hasmorrhagic  form,  223 

paralytic  forms,  220 

pleuritic  form,  226 

pneumonic  form,  223 

syncopal  form,  224 

tetanic  form,  220 

typhoid  form,  218 
Phagocytosis,   cells  concerned  in,    134, 

.J35 

significance  of,  136 


474 


GENERAL    INDEX. 


Phagocytosis,    time    of  occurrence    of, 

136 
Phagocytes,  varieties  of,  135 

degeneration  of,  135 

substances  engulfed  by,   136 
Pigment,  in  tertian  plasmodia,  20 

diagnostic  value  of,  321 

in  aestivo-autumnal plasmodia,  36, 

38 
in  quartan  plasmodia,  27 

Plasmodia,  discovery  of,  6 

biology  of,  19,  26,  35,  37,  40 

cultivation  of,  92 

demonstration  of,  in  blood,  3  1 1 

in  sections,  320 

destruction  of,  343 

extracorporeal    existence    of,    40, 

58 
objects  mistaken  for,  318,  319 

resistance  of,  343 

species  of,  1 5 

staining  of,  22,  29,  39,  312 
Plasmodium  vivax  (tertian),  19 

action  of  quinine  on,  364 

cultivation  of,  92 

development  of,  20,  56 

differential  diagnosis  of,  319 

gametes  of,  43,  370 

history  of,  19 

hyaline  forms  of,  20,  22 

in  latent  infections,  161,  228 

intracorpuscular    conjugation    in, 
246 

macrogametes  of,  43 

microgametes  of,  44 

microgametocytes  of,  43 

movement  of,  20 

pigmented  forms  of,  20,  22 

pigment  of,  20,  22 

protoplasm  of,  21,  22 

size  of,  20 

sporogenic  forms  of,  42 

sporulating  forms  of,  21,  22 

staining  reactions  of,  22 

structure  of,  22 
Plasmodium  malariaz  (quartan),  27 

band  forms  of,  30 

cultivation  of,  92 

development  of,  27,  48,  56 

differential  diagnosis  of,  319 

gametes  of,  48,  370 

history  of,  26 

hyaline  forms  of,  27,  29 

macrogametes  of,  48 

microgametes  of,  48 

microgametocytes  of,  48 

movement  of,  27 

pigmented  forms  of,  27,  29 

pigment  of,  27,  29 

protoplasm  of,  27,  29 

quinine  and,  368 

size  of,  27 

sporogenic  forms  of,  47 

sporulating  forms  of,  28 

staining  reactions  of,  29 

structure  of,  29 


Plasmodium  falciparum  (tertian  aestivo- 
autumnal),  37 

cultivation  of,  92 

development  of,  37,  56 

differential  diagnosis  of,  320 

gametes  of,  48,  370 

history  of,  34 

hyaline  forms  of,  37,  39 

in  latent  infections,  161,  228 

»nicrogametes  of,  50,  52 

■microgametes  of,  51,  53 

microgametocytes  of,  51,  52 

movement  of,  38 

pigmented  forms  of,  38,  39 

pigment  of,  38,  39 

protoplasm  of,  38,  39 

quinine  and,  369 

size  of,  38 

sporogenic  forms,  48 

sporulating  forms  of,  39 

staining  reactions  of,  39 

structure  of,  39 
Plasmodium    falciparum     quotidianum 
(quotidian  aestivo-autumnal), 

35 

cultivation  of,  92 

development  of,  35,  56 

differential  diagnosis  of,  320 

gametes  of,  48,  370 

history  of,  34 

hyaline  forms  of,  3  5 

in  latent  infections,  161,  228 

macrogametes  of,  50,  52 

microgametes  of,  51,  53 

microgametocytes  of,  51,  52 

movements  of,  36 

pigmented  forms  of,  36,  39 

pigment  of,  36,  39 

protoplasm  of,  36,  39 

quinine  and,  369 

size  of,  3  5 

sporogenic  forms  of,  48 

sporulating  forms  of,  37 

staining  reactions  of,  39 

structure  of,  39 
Pleurisy,  occurrence  of,  226,  277 
Pneumonic  septicaemia,  277 
Pneumonia,  brocho-,  276 

fibroid,  277 

lobar,  276 

malarial,  223 
Polyuria,  occurrence  of,  271 
Prognosis,  factors  influencing,  298 

age  and,  299 

general  consideration  of,  298 

in  aestivo-autumnal  malaria,  299, 

3°°  . 

in  complications,  302 
in  malarial  cachexia,  302 
in  pernicious  malaria,  300 
in  quartan  malaria,  299 
in  sequelae,  302 
in  subcontinued  forms,  301 
in  tertian  malaria,  299 
locality  and,  298 
occupation  and,  299 


GENERAL    INDEX. 


475 


Prognosis,     physical     conditions     and, 
299 

race  and,  298 

social  conditions  and,  299 
Predisposition,  age  in,  114 

altitude  in,  105 

atmospheric  conditions  in,  112 

climate  in,  104 

locality  in,  104 

moisture  in,  106 

occupation  in,  114 

race  in,  113 

rain  in,  108 

season  in,  109 

sex  in,  113 

social  conditions  in,  114 

soil  in,  106 

time  of  day  in,  106 

winds  in,  108 
Prophylaxis,   general  consideration  of, 
342 

biological  methods  of,  348 

chemical  methods  of,  351 

destruction  of  plasmodia,  343 
of  mosquitoes,  347 

drainage  in,  351 

education  regarding,  3  56 

isolation  of  patient,  3  53 

physical  methods  of,  351 

screening  in,  3  54 

summary  of  methods  of,  357 

use  of  quinine  in,  343 
Protozoa,  conjugation  in,  247 
Puerperal  fever,  malaria  mistaken  for, 
281 

occurrence  of,  280 
Pulse,  in  tertian  cases,  171 

in  aestivo-autumnal  cases,  180 

in  quartan  cases,  175 
Pyaemia,  differential  diagnosis  of,  335 
Pyelitis,  occurrence  of,  335 

Quartan  malaria,  26,  175 

diagnosis  of,  330 

frequency  of,  175 

Plasmodium  of,  26,  47 

prognosis  of,  299 

sub-continued  form  of,  252 

symptoms  of,  175,  252 

treatment  of,  360 

typhoid  and,  287 
Quinine,  history  of,  360 

action  of,  on  plasmodia,  361 

as  a  test  for  malaria,  307 

contraindications  to,  378 

dosage  of,  376 

effect  on  temperature  curves  of  ,  1 84 

eruptions  due  to,  379 

methods  of  giving,  373 

preparations  of,  371 

salts  of,  371 

substitutes  for,  378 

time  of  administration  of,  371 
Quotidian    aestivo-autumnal    malaria, 
35.  182 

diagnosis  of,  330 


Quotidian    aestivo-autumnal    malaria, 
frequency  of,  176 
illustrative  cases  of,   [95 
Plasmodium  of,  3  5,  48 
prognosis  of,  299 
symptoms  of,  182,  252 
treatment  of,  360 


Race  and  predisposition,  1 13 

and  prognosis,  298 
Recovery,  spontaneous,  259 

conjugation  and,  261 

etiology  of,  260 
Recurrences,  occurrence  of,  239 

conjugation  and,  245 

etiology  of,  244 

time  of,  239 
Relapsing  fever,  parasites  of,  413 

differential  diagnosis  of,  335 
Respiratory  system,  276 

complications  in,  276 
Retina,  malarial  diseases  of,  150,  273 
Rheumatism,  acute,  280 


Sacharoff 's  classification,  1  5 

Salochinin,  380 

Schaudinn's  classification,  16 

Schistosoma  hcsmatobium,  281 

Schizogony,  occurrence  of,  18 

Schizont,  structure  of,  22,  29,  39 

of  quartan  plasmodium,  27,  29 
of  quotidian  aestivo-autumnal  Plas- 
modium, 3  5,  39 
of  tertian  aestivo-autumnal   Plas- 
modium, 38 
of  tertian  plasmodium,  20,  22 

Schuffner's  dots,  26,  31,  40 

Season,  relation  to,  85,  109 

Septicaemia,  occurrence  of,  277 

Sequela?,  267 

of  the  circulatory  system,  269 

of  the  gastro-intestinal  system,  269 

of  the  genito-urinary  system,  270 

of  the  glandular  system,  271 

of  the  nervous  system,  267 

of  the  organs  of  special  sense,  273 

other  sequelae,  274 

Serum  therapy,  385 

Skin,   symptoms  connected  with,    188, 
274 
diseases  of,  281 

Species,  of  plasmodia,  14 
diagnosis  of,  330 
interchangeability  of,  14 

Spinal  cord,  pathology  of,  1  50 

Spirochaetes,  description  of,  445 
biological  position  of,  446 
cultivation  of,  451 
demonstration  of,  457 
distribution  of,  in  man,  456 
geographical  distribution  of,  446 
immunity  to,  453 
morphology  of,  447 
pathogenicity  of,  451 


476 


GENERAL    INDEX. 


Spirochetes, 

Spirochata  plicatilis,  447 

recurrcntis,  447 
carter  i,  450 
duttoni,  448 
novyi,  450 

transmission  of,  454 
Spleen,  floating,  272 

abscess  of,  272 

crescents  in,  1  54 

enlargement  of,  154,  igo 

free  plasmodfa  in,  1  54 

focal  necrosis  in,   1  55 

haemorrhage  in,   1  54 

macrophages  in,  1  54 

pathology  of,  1  54 

phagocytes  in,  154,  155 

pigment  in,  1  54 

puncture  of,  322 

rupture  of,  272 
Sporoblasts,  description  of,  60 
Sporogony,  description  of,  56 
Sporonts,    58 
Sporozoites,  description  of,  60 

staining  of,  62 
Sporulation,  description  of,  21,  28,  37, 

39 

in  aestivo-autumnal  plasmodia,  3  7 , 

39 
in  quartan  plasmodium,  28 
in  tertian  plasmodium,  2  1 
relation  of,  to  paroxysms,  144 
Staining  of  plasmodia,  22,  29,  39,  312 
of  aestivo-autumnal  plasmodia,  39, 

3*3 

of  quartan  plasmodium,  29,  312 

of  sporogenic  forms,  51,  318 

of  tertian  plasmodium,  22,  312 

Giemsa's  method  of,  317 

Leishman's  method  of,  315 

Marino's  method  of,  316 

methods  of,  313 

Nocht's  method  of,  315 

Plehn's  method  of,  316 

Romanowsky's  method,  314 

Wright's  method  of,  313 
Stomach,  pathology  of,  152 
Sub-continued  fever,  252 

prognosis  of,  301 

symptoms  of,  2  53 
Sweats  in  malaria,  173 

in  quartan  fever,  176 

in      quotidian      aestivo-autumnal, 
182 

in  tertian  aestivo-autumnal,  180 

in  tertian  fever,  173 
Symptomatology,  1 7 1 

analysis  of,  184 

of  malarial  cachexia,  2  58 

of  quartan  fever,  175 

of    quotidian    aestivo-autumnal 
fever,  182 

of  pernicious  infections,  215 

of  tertian  aestivo-autumnal  fever, 
180 

of  tertian  fever,  171 


Temperature,  discussion  of,  144,  219 

analysis  of,  184 

atypical  temperature  curves,  184 

cause  of  atypical  curves,  184 

in  quartan  fever,  1  7  5 

in  tertian  aestivo-autumnal  fever, 
180 

in      quotidian      aestivo-autumnal 
fever,  182 

in  tertian  fever,   1  7  1 
Tertian  malaria,  19,  161 

diagnosis  of,  330 

frequency  of,  171 

Plasmodium  of,  19,  42 

prognosis  of,  299 

recurrences  in,  243 

symptoms  of,  171,  252 

treatment  of,  360 
Tertian  aestivo-autumnal   malaria,  37, 
163,  180,  194 

clinical  illustrations  of,  203 

diagnosis  of,  330 

frequency  of,  176 

plasmodium  of,  37,  48 

prognosis  of,  300 

symptoms  of,  180,  253 

treatment  of,  360 
Tinnitus  aurium,  378 
Tongue,  characters  of,  188 
Tonsillitis,  occurrence  of,  281 
Toxin,  malarial,  143,  145 

relation  to  fever,  144 
Transmission  of  malaria,  79 

by  air,  79 

by  inoculation  of  malarial  blood,  83 

by  mosquitoes,  84 

by  water,  81 
Treatment  of  malaria,  360 

aristochin  in,  380 

Esanophele  in,  383 

euchinin  in,  380 

methylene  blue  in,  380 

phenocoll  in,  380 

quinine  in,  361 

Roentgen's  rays  in,  384 

salochinin  in,  380 

serum  therapy,  385 

substitutes  for  quinine,  378 

Warburg's  tincture  in,  384 

of  cachexia,  382 

of  convalescence,  381 

of  pernicious  fevers,  382 

of  special  symptoms,  381 
Trophozoites,  20 
Trypanosoma  gambiense,  428 

blood  in  infections  with,  439 

biology  of,  436 

biological  position  of,  430 

cultivation  of,  434 

demonstration  of,  439 

distribution  in  man  of,  438 

examination       of       cerebro-spinal 
fluid,  439 

geographical  distribution  of,  430 

gland  puncture  in  infections  with, 
441 


GENERAL    INDEX. 


477 


Trypanosoma  gambiense, 

history  of,  428 

intermediate  host  of,    435 

morphology  of,  430,  433 

multiplication  of,  434 

pathogenicity  of,  437 

staining  of,  442 

transmission  of,  438 
Trypanosoma  lewisi,  442 

brucei,  442 

dimorphon,  442 
■  equinum,  442 

equiperdum,  442 

evansi,  442 

theileri,  442 
Trypanosomiasis,    differential    diagno- 
sis of,  335 
Tuberculosis,  as  complication,  277 

differential  diagnosis  of,  335 
Typhoid  and  malaria,  280,  284 

differential  diagnosis  of,  332 

Ulcers,  gastric,  269 

Uninhabited  regions  and  malaria,  115 

Urinary  system,   symptoms  connected 

with,  190 
Urine,  changes  in,  140 

acidity  of,  140 

albumin  in,  142 

chlorides  in,  142 

color  of,  141 

Diazo  reaction  in,  142 


Urine,  indican  in,  142 

iron  in,  142 

nucleo-albumin  in,  142 

pepton  in,  142 

phosphates  in,  141 

quantity  of,  140 

reaction  of,  141 

sodium  and  potassium  in,  142 

specific  gravity  of,  141 

total  solids  of,  141 

toxicity  of,  142 

urea  in,  141 

uric  acid  in,  141 
Urticaria,  occurrence  of,  188 

Vacuoles,  differentiation  of,  310 
Vegetable  organisms  and  malaria,  5 
Vertigo,  occurrence  of,  191,  274 
Viscera,  pathology  of,  149 
Vomiting,  occurrence  of,  184,  382 
treatment  of,  382 

Warburg's  tincture,  384 
Water,  transmission  by,  81 

experiments  with,  82 
Winds,  relation  of,  81,  108 

Yellow  fever,  differential  diagnosis  of, 
333 

Zygote,  malarial,  demonstration  of,  327 


RC156 


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